The role of retrograde signals during plant stress responses

The role of retrograde signals during plant stress responses Abstract Chloroplast and mitochondria not only provide the energy to the plant cell but due to the sensitivity of organellar processes to perturbations caused by abiotic stress, they are also key cellular sensors of environmental fluctuations. Abiotic stresses result in reduced photosynthetic efficiency and thereby reduced energy supply for cellular processes. Thus, in order to acclimate to stress, plants must re-program gene expression and cellular metabolism to divert energy from growth and developmental processes to stress responses. To restore cellular energy homeostasis following exposure to stress, the activities of the organelles must be tightly co-ordinated with the transcriptional re-programming in the nucleus. Thus, communication between the organelles and the nucleus, so-called retrograde signalling, is essential to direct the energy use correctly during stress exposure. Stress-triggered retrograde signals are mediated by reactive oxygen species and metabolites including β-cyclocitral, MEcPP (2-C-methyl-d-erythritol 2,4-cyclodiphosphate), PAP (3ʹ-phosphoadenosine 5ʹ-phosphate), and intermediates of the tetrapyrrole biosynthesis pathway. However, for the plant cell to respond optimally to environmental stress, these stress-triggered retrograde signalling pathways must be integrated with the cytosolic stress signalling network. We hypothesize that the Mediator transcriptional co-activator complex may play a key role as a regulatory hub in the nucleus, integrating the complex stress signalling networks originating in different cellular compartments. Abiotic stress, energy metabolism, Mediator complex, photosynthesis, reactive oxygen species, retrograde signalling Introduction In the first half of the 21st century, the world’s population is predicted to surpass 9 billion, and the issue of obtaining food security for this massive population is becoming increasingly compounded by changes to our climate, constituting perhaps one of the greatest challenges our society has ever faced (Thornton et al., 2014). Plants are often exposed to unfavourable or stressful conditions in their growth environment, and have evolved sophisticated means by which they can survive and reproduce under abiotic stress conditions such as water deficit, high salt concentrations, and temperature extremes. Extreme growth conditions will become more common in the future as a result of changing land use and atmospheric composition (Fedoroff et al., 2010; Sterling et al., 2012). Thus, the natural evolutionary and plastic responses of plants upon which we are so dependent may not be enough to keep pace with the rapid rate of climate change (Franks et al., 2014). It is therefore crucial that we focus on elucidating the regulatory components and molecular mechanisms involved in acclimation and adaptation to stress conditions, as this knowledge will give rise to concrete biotechnological and agricultural advances for plant breeding and the engineering of plants with enhanced tolerance. Acclimation to stress conditions requires a metabolic and energetic investment, and this usually comes at the expense of energy available for growth and development (Baena-González, 2010). This review will focus on the role of organelles and retrograde signalling (RS) during the response to abiotic stress conditions, with emphasis on the recovery of cellular energy metabolism. Retrograde signals involved in operational control The organelles play critical roles as sensors of changes in the growth environment, and high crop yields are closely associated with the capacity to maintain photosynthesis and cellular metabolism during stress (Fernández and Strand, 2008). The chloroplasts and the mitochondria are the power-houses of the plant cell. Photosynthesis provides the energy, oxygen, and reduced carbon required for most life on our planet, yet the photosynthetic reactions housed in the chloroplasts are extremely sensitive to changes in the growth environment (Huner et al., 1998; Bode et al., 2016). Abiotic stress conditions cause photoinhibition of PSII and inhibition of the enzymes involved in carbon assimilation (Murata et al., 2007). In the mitochondria, aerobic respiration and oxidative phosphorylation provide ATP required for cellular functions, and these reactions are also highly sensitive to stress conditions. Exposure to abiotic stress results in a decrease in the overall efficiency of photosynthesis and respiration, and, as a consequence, cellular energy supply. Thus, it is essential for plants to restore their energy homeostasis via recovery of perturbed photosynthesis and respiration if they are to survive the stress. These responses require an adjustment of gene expression and metabolism towards defence and acclimation, which demands a distribution of energy away from biosynthetic growth and development processes (Baena-González, 2010). The progenitors of chloroplasts and mitochondria were thought to have once existed as free-living prokaryotic organisms, and were integrated into ancestral eukaryotic cells through endosymbiosis. During evolution, the functional control of these endosymbionts was acquired by the nucleus along with most of their genome. However, a small, independently replicating genome has been retained in each organelle, which encodes a small number of proteins required for organellar function (Dyall, 2004; Barajas-López et al., 2013). The activities of these genomes must be co-ordinated with gene expression in the nucleus to enable proper organellar function and energy metabolism, especially during stress exposure. This requires communication between the organelles and the nucleus, both anterograde (nucleus to organelle) and retrograde (organelle to nucleus) communication. Retrograde communication is a vital and continuous process throughout the life of the plant. The types of active signalling pathways and the responses are modulated according to the developmental and metabolic status of the plant. Retrograde signals can be divided into ‘biogenic’, referring to signals generated by the plastid as it develops from a proplastid or etioplast into a chloroplast, and ‘operational’ signals, including those generated from a mature chloroplast in response to environmental perturbations (Chan et al., 2016b). A recent meta-analysis of transcriptomes indicated that of the genes differentially regulated in response to abiotic stress, between 10% and 20% encode proteins localized to the chloroplasts, emphasizing the important role of these organelles during plant stress responses (Kmiecik et al., 2016). In this review, we will focus on the role of the operational retrograde signals in mediating the transcriptional response to abiotic stress conditions. Reactive oxygen species (ROS), a source of oxidative stress and second messengers Following exposure to various stress conditions, accumulation of ROS is very common. These oxygen derivatives have an increasingly appreciated dual role: as unwanted by-products of cellular metabolism they interact with and can destroy functional proteins, lipids, and metabolites through oxidative degradation, yet evolution has harnessed ROS as essential messengers in signal transduction (Schmitt et al., 2014; Mignolet-Spruyt et al., 2016). Production or transfer of reducing equivalents or electrons during photosynthesis and respiration inevitably generates ROS in the chloroplast, mitochondria and peroxisomes, and ROS generation increases during stress conditions due to suboptimal function of the components of the electron transport chains (ETCs) (Møller and Sweetlove, 2010; Cruz de Carvalho, 2008). ROS can transduce information from the organelles regarding the activity and redox state of the photosynthetic and respiratory ETCs, and integrate with and initiate signalling pathways in response to abiotic and biotic fluctuations in the environment (Barajas-López et al., 2013; Huang et al., 2016). ROS with known signalling functions include singlet oxygen (1O2), superoxide anion radical (O2–·), and hydrogen peroxide (H2O2) (Laloi et al., 2004; Corpas et al., 2017). Efficient photosynthesis depends on a tightly regulated balance between utilization and dissipation of light energy, and between the rates of damage and repair of the PSII complex (Takahashi and Murata, 2008). Transfer of excitation energy from triplet chlorophylls (such as the P680 reaction centre chlorophylls in PSII) to molecular oxygen causes the generation of singlet oxygen and photo-oxidative damage to the oxygen-evolving complex (OEC) and the D2 and particularly D1 subunits of PSII (Murata et al., 2007; Kale et al., 2017). PSII is one of the main sites of 1O2 generation in the cell and the initiation point of a signalling cascade (Fig. 1). Abiotic stresses can also cause inhibition of the highly efficient PSII repair pathway by inactivation of the translational machinery (which prevents the synthesis of replacement D1 polypeptides), as the thioredoxin-regulated translation factor EF-G required for D1 synthesis is specifically inhibited by H2O2 (Kojima et al., 2007; Takahashi and Murata, 2008; Nishiyama et al., 2011). In the chloroplast, H2O2 is generated via enzymatic dismutation of O2–· or reduction by plastoquinol (PQH2), the reduced form of plastoquinone (PQ), which also functions as an antioxidant while its oxidized form serves as an electron carrier upstream of the cytochrome b6f complex (Dietz et al., 2016) (Fig. 1). H2O2 may antagonize 1O2 signalling by maintaining QA (the primary electron acceptor quinone of PSII) in an oxidized state, thus keeping P680-mediated 1O2 generation at a low level (reviewed in Barajas-López et al., 2013). H2O2 is also formed as a by-product of metabolism in the peroxisomes, such as photorespiration by glycolate oxidase (GOX) or fatty acid β-oxidation through ATP-binding cassette (ABC) transporters and acetyl-CoA (Corpas et al., 2017). Superoxide radicals are generated at the acceptor side of illuminated PSI via the Mehler reaction, and the generation increases during carbon limitation or inhibition of Rubisco (Takahashi and Murata, 2008). Inhibition of Rubisco and limitation of carbon fixation are exacerbated by cold, heat, and salt stress, resulting in accumulation of reduced electron carriers at the acceptor side of PSI, such as NADPH. These electrons may be transferred to molecular oxygen, resulting in an increase in the generation of O2–· and thus H2O2 (via dismutation), which further increases PSII photoinhibition (Takahashi and Murata, 2008; Takahashi and Badger, 2011; Nishiyama and Murata, 2014) (Fig. 1). Fig. 1. View largeDownload slide Sites of ROS production in the chloroplast and the associated stress responses. The photosynthetic electron transport chain is one of the main sources of ROS, especially under stress conditions. Red arrows indicate abiotic stress-induced changes related to the photosynthetic apparatus. Singlet oxygen (1O2) from PSII, can be quenched by β-carotene (β-car) and through the non-enzymatic cleavage of β-car forming β-cyclocitral (β-CC) which, through the mediation of MBS1, acts as a secondary messenger and influences 1O2-responsive gene (SORG) expression. Alternatively the 1O2 signaling pathway is activated by EXECUTER1/EXECUTER2 (EX1/EX2). The two, most probably independent, pathways are physically separated within the grana: while the β-CC pathway takes place in the grana core, EX1 and EX2 are found in the margin regions of the grana. 1O2 is transformed into the less harmful hydrogen peroxide (H2O2) through the superoxide radical (O2–·). H2O2 also originates directly from plastoquinol (PQH2) and the cytochrome b6f complex (cyt b6f), while PSI is responsible for O2–· production, which can lead to H2O2 formation or programmed cell death (PCD). H2O2 is able to cross membranes through specific channels, called peroxiporins. Fig. 1. View largeDownload slide Sites of ROS production in the chloroplast and the associated stress responses. The photosynthetic electron transport chain is one of the main sources of ROS, especially under stress conditions. Red arrows indicate abiotic stress-induced changes related to the photosynthetic apparatus. Singlet oxygen (1O2) from PSII, can be quenched by β-carotene (β-car) and through the non-enzymatic cleavage of β-car forming β-cyclocitral (β-CC) which, through the mediation of MBS1, acts as a secondary messenger and influences 1O2-responsive gene (SORG) expression. Alternatively the 1O2 signaling pathway is activated by EXECUTER1/EXECUTER2 (EX1/EX2). The two, most probably independent, pathways are physically separated within the grana: while the β-CC pathway takes place in the grana core, EX1 and EX2 are found in the margin regions of the grana. 1O2 is transformed into the less harmful hydrogen peroxide (H2O2) through the superoxide radical (O2–·). H2O2 also originates directly from plastoquinol (PQH2) and the cytochrome b6f complex (cyt b6f), while PSI is responsible for O2–· production, which can lead to H2O2 formation or programmed cell death (PCD). H2O2 is able to cross membranes through specific channels, called peroxiporins. ROS transduction, recognition, and transcriptional responses Different ROS have different lifetimes and activities, and can trigger specific and generic responses depending on the compartment in which they are generated and the cellular environment with which they interact. Steady-state cellular ROS levels are under strict regulation by a dynamic and redundant network of ~152 genes in Arabidopsis, including ROS-generating and -scavenging enzymes (Mittler et al., 2004; Gechev et al., 2006). In plants with compromised levels of ROS-scavenging enzymes, or plants that were treated with ROS-generating agents, transcriptome analyses revealed unique source-specific groups of genes responding to the different treatments (Mittler et al., 2004; Gadjev et al., 2006; Møller and Sweetlove, 2010). This ROS identity-specific gene expression response was also confirmed by Affymetrix gene chip data, differentiating three clusters within 1206 differentially expressed genes; where 70 genes proved to be exclusively 1O2 responsive (cluster I), 9 genes responsive only to H2O2 (cluster II), and 31 genes responsive to both (cluster III) (op den Camp et al., 2003). The specific cellular response to ROS-mediated signalling depends on several factors: the type, dose, timing, and duration of the ROS signal and the site of the ROS generation (Gechev et al., 2006). Although various studies revealed that high doses of O2–· and H2O2 can trigger programmed cell death (PCD), while low doses generate acclimation responses against oxidative and abiotic stress, little is known about how specific ROS signals are perceived and how the appropriate transcriptional response is induced (Gechev et al., 2002; Vranová et al., 2002). It is thought that abiotic stresses, including drought, salinity, heat, and high light, produce distinctive global ROS signatures which can be perceived by appropriate receptors to induce the response required for the particular stress (Choudhury et al., 2016). Indeed, certain TFs are able to respond specifically to one type of ROS, but may also be influenced by the global ROS environment (Gadjev et al., 2006). H2O2 is able to cross biological membranes and migrate from its production site, most probably through H2O2-specific aquaporin channels, called peroxiporins (Henzler and Steudle, 2000; Bienert et al., 2006; Tian et al., 2016) (Fig. 1). In the nucleus, known targets of the H2O2-specific signalling pathway include metabolism- and immune response-related genes, such as cytochrome P450, PAL1, and GST6, and TFs including DEHYDRATION RESPONSIVE ELEMENT BINDING 2A (DREB2A), zinc finger transcription factor of Arabidopsis thaliana 12 (ZAT12), and members of the WRKY, basic helix–loop–helix (bHLH), heat shock protein (HSP), and mitogen-activated protein kinase (MAPK) cascade families (reviewed in Gadjev et al., 2006). Multiple lines of evidence suggest that H2O2-induced transcriptional responses occur in two stages: first, a quick activation of specific TFs such as ZAT12, followed by the induction of many downstream target genes in order to reach induction of full stress tolerance. The 1O2-responsive genes represent the largest single type of ROS-induced group (Gadjev et al., 2006). A specific function for 1O2 was discovered using the conditional flu (fluorescent in blue light) mutant of Arabidopsis, which contains a lesion in a regulatory protein of the tetrapyrrole biosynthesis pathway (TBP) and accumulates the intermediate protochlorophyllide in the dark. Upon transition of the flu mutant to light, a burst of 1O2 occurs which activates the expression of nuclear-encoded genes, many of which are involved in the stress acclimation response and PCD (Meskauskiene et al., 2001; Danon et al., 2005; Wang et al., 2016). Mor et al. (2014) also showed, using bioinformatic tools, that the transcriptomes of many stresses are correlated with the transcriptome described for the 1O2-producing flu mutant, suggesting that 1O2 is a common factor in many stress-induced signalling pathways. Due to its very short half-life (~200 ns) and strong reactivity, 1O2 itself is unlikely to be the retrograde signal; however, 1O2 may induce the generation of second messengers by oxidative modification of lipids, proteins, or pigments (Schmitt et al., 2014). To date, two 1O2-triggered signalling pathways have been revealed which transmit source-specific signals between the chloroplast and the nucleus (Møller and Sweetlove, 2010; Cruz de Carvalho, 2014). Carotenoid pigments such as β-carotene function as quenchers of 1O2 within the photosynthetic reaction centres and antennae (Triantaphylidés et al., 2008; Ramel et al., 2012a; Staleva et al., 2015). Non-enzymatic cleavage of β-carotene by 1O2 forms the volatile β-cyclocitral (β-CC) which, through the mediation with the downstream METHYLENE BLUE SENSITIVITY 1 (MBS1) protein (Shao et al., 2013; Shumbe et al., 2017), can act as a second messenger, influencing the expression of a set of 1O2-responsive genes (SORGs) (Ramel et al., 2012a, b) (Fig. 1). Another 1O2 signalling pathway requires the function of two nuclear-encoded and chloroplast-targeted proteins, EXECUTER1 (EX1) and EX2, to transfer the signal to the nucleus and regulate SORG expression. Inactivation of both EX1 and EX2 results in almost complete repression of SORGs (Wagner et al., 2004; Lee et al., 2007). It was recently shown that proteolysis of EX1 by the thylakoid metalloprotease FtsH2 is a critical early step in 1O2-triggered signalling (Wang et al., 2016). Interestingly, this process is spatially and functionally associated with the FtsH2-mediated PSII repair pathway, localized to the grana margins. In contrast, the β-CC-mediated 1O2 signalling pathway is initiated from the operational PSII reaction centres in the grana core (Bailey et al., 2002; Ramel et al., 2012b; Wang et al., 2016) (Fig. 1). Comparative analysis of transcripts regulated by these two separate mechanisms supports the existence of two independent signalling pathways, with only 20 genes in common (including WRKY33, WRKY40, and SIB1 TF genes) (Dogra et al., 2017). However, the reason for the co-existence of these two 1O2-triggered RS pathways, and whether they act truly independently from each other, remains to be elucidated. Tetrapyrrole biosynthesis and chloroplast retrograde signalling One of the plastid signals induced by oxidative stress is linked to tetrapyrrole biosynthesis, although the exact nature of this signal(s) has been debated for many years. Higher plants synthesize four major tetrapyrrole molecules—chlorophyll, haem, sirohaem, and phytochromobilin—via a common branched pathway in the plastids. While the biosynthetic pathway has common steps in the generation of early intermediates from the initial precursor glutamate, the flux through the Mg2+ (chlorophyll) and/or Fe2+ (haem and its linearized derivatives, bilins) branches of the pathway is carefully regulated at multiple levels (Kobayashi and Masuda, 2016). A tightly regulated synthesis is essential as many tetrapyrroles are excited by light and, if left unquenched, they can form highly toxic radicals. Changes to the flux through the TBP are indicators of developmental and environmental changes, and perturbations in the TBP have been shown to affect expression of photosynthesis-associated nuclear-encoded genes (PhANG genes) in both green algae and higher plants (Johanningmeier and Howell, 1984; Kropat et al., 1995, 1997, 2000; Strand et al., 2003; Alawady and Grimm, 2005; Pontier et al., 2007; von Gromoff et al., 2008; Zhang et al., 2011; Ibata et al., 2016). Arabidopsis mutants with impaired communication between the chloroplast and the nucleus, referred to as the gun (genomes uncoupled) mutants, were isolated from forward genetic screens (Susek et al., 1993; Mochizuki et al., 2001; Woodson et al., 2011). The gun mutants maintain expression of PhANG genes when exposed to oxidative stress, whereas wild-type plants demonstrate strong suppression of PhANG expression under the same conditions (Susek et al., 1993; Woodson et al., 2011). GUN2–GUN5 all encode components affecting the flux through the chlorophyll branch of the pathway, and the respective mutants all have a pale phenotype. GUN6, on the other hand, encodes ferrochelatase I of the haem biosynthesis pathway, and may induce an antagonistic signal to GUN2–GUN5 (von Gromoff et al., 2008; Woodson et al., 2011). Environmental changes affect the flux through the TBP, causing perturbations and accumulation of both ROS and specific intermediate metabolites, and mutants such as gun5 are more sensitive to abiotic stresses such as exposure to low temperatures (Kindgren et al., 2015). In particular, the aerobic cyclase reaction was shown, both in Arabidopsis and in cucumber, to be extremely sensitive to oxidative stress and ROS, resulting in the accumulation of upstream intermediates such as Mg protoporphyrin IX (MgProtoIX)/MgProtoIX-methylester (Aarti et al., 2006; Stenbaek et al., 2008) (Fig. 2). Accumulation of these intermediates was also observed in the crd mutant of Arabidopsis, which contains a mutation in the CHL27 gene encoding a putative cyclase subunit (Bang et al., 2008). These intermediates may leave the chloroplast by an unknown transporter, interact with and inhibit the ATPase activity of an HSP90 chaperone complex in the cytosol, and subsequently regulate expression of specific nuclear genes through regulation of the TFs LONG HYPOCOTYL5 (HY5) and PSEUDO RESPONSE REGULATOR 5 (PRR5) via ZEITLUPE (ZTL) (Fig. 2) (Kindgren et al., 2011, 2012; Norén et al., 2016). It was recently demonstrated that binding of ProtoIX to the GUN4 protein increased the production of 1O2, suggesting a connection between the tetrapyrrole-mediated signal and the EX1/EX2 proteins (Fig. 2) (Adhikari et al., 2009; Tarahi Tabrizi et al., 2016). Indeed, 1O2 generation from chlorophyll biosynthesis intermediates was recently proposed to initiate an EX1/EX2-mediated inhibitory retrograde signal, suppressing PhANG expression during seedling de-etiolation (Page et al., 2017). Furthermore, RNAi-mediated reduction of key enzymes in the chlorophyll biosynthesis pathway revealed a complex and time-dependent interplay between metabolite- and ROS-mediated RS processes (Schlicke et al., 2014). MEcPP-mediated retrograde signalling and ER stress Another plastid-derived signal mediated by a small metabolite is the 2-C-methyl-d-erythritol 2,4-cyclodiphosphate- (MEcPP) mediated signal, which has been confirmed as an operational retrograde signal produced in response to oxidative stress. A forward genetics approach identified the constitutively expressing hydroperoxide lyase1 (ceh1) mutant of Arabidopsis, which contains a lesion in the enzyme 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (HDS). This enzyme catalyses a rate-limiting reaction in the isoprenoid biosynthesis pathway, and ceh1 plants accumulate the intermediate MEcPP as a result (Fig. 2) (Xiao et al., 2012). Analyses of the transcriptome and proteome of ceh1 mutant plants indicated that MEcPP induced the expression of nuclear-encoded stress-responsive genes, including non-PhANG chloroplast-localized proteins and proteins involved in the response to endoplasmic reticulum (ER) stress (Xiao et al., 2012; Walley et al., 2015). The HDS enzyme contains a [4Fe–4S] cluster which makes it highly sensitive to oxidative stress, and accumulation of MEcPP has also been observed in wild-type plants in response to oxidative stress, high light, and wounding (Seemann et al., 2005). Furthermore, it was shown that MEcPP could act as a retrograde signal to induce the expression of nuclear genes encoding proteins involved in stress response and biotic defence signalling, including the plastid-localized hydroperoxide lyase (HPL) enzyme, involved in the biosynthesis of jasmonic acid (JA) (Xiao et al., 2012; de Souza et al., 2017) (Fig. 2). Overaccumulation of MEcPP in stressed wild-type or ceh1 plants was also suggested to result in reduced growth and early flowering, mediated via the B-box TF B-box protein 19 (BBX19) (Wang et al., 2015; de Souza et al., 2017). Two recent reports revealed that the MEcPP-mediated retrograde signal provides a mechanism for induction of the ER stress response. The accumulation of unfolded or misfolded proteins in the ER occurs as a consequence of exposure to both abiotic and biotic stress. The accumulation is sensed by sensor proteins as ER stress, and a series of sophisticated compensatory mechanisms called the unfolded protein response (UPR) is initiated (Liu and Howell, 2016). The UPR consists of an up-regulation of molecular chaperone and folding cofactors, 26S ubiquitin proteasome-mediated ER-associated degradation (ERAD), and suppression of protein translation. UPR is elicited by two pathways, one mediated by the ER-localized mRNA splicing factor INISITOL REQUIRING 1 (IRE1) and the TF basic leucine zipper 60 (bZIP60), and the another mediated by binding immunoglobulin proteins (BiPs) and the TFs bZIP28 and bZIP17 (Deng et al., 2011; Srivastava et al., 2013; reviewed in Bao and Howell, 2017). MEcPP was shown to activate the UPR by directly inducing the expression of bZIP60 and IRE1a, and bZIP28 and BiP3, via the nuclear TF CALMODULIN-BINDING TRASCRIPTIONAL ACTIVATOR 3 (CAMTA3) in a Ca2+-dependent manner (Fig. 2) (Walley et al., 2015; Benn et al., 2016). Fig. 2. View largeDownload slide Metabolite-mediated retrograde signalling pathways triggered by abiotic stress. Three major pathways discussed in the text are shown. Drought, wounding, and high light stress induce the generation of ROS in the chloroplast, primarily from the photosynthetic electron transport chain. ROS may alter the chloroplastic redox state by oxidative modifications, which can inhibit the activity of specific enzymes in biosynthetic pathways, including SAL1, HDS, and the Mg-protoporphyrin monomethylester aerobic cyclase (CHL27), resulting in the accumulation of intermediate metabolites, including PAP, MEcPP, and MgProtoIX (/-ME). PAP is exported to the cytosol by the bidirectional transporter PAPST1 and may accumulate in the nucleus where it inhibits the activity of XRNs, altering RNA splicing and processing; PAP may also regulate the expression of stress response genes and calcium signalling components via unknown factors. Drought stress induces ABA signalling, which interacts with calcium signalling to regulate stomatal closure via the SLAC1 anion channel, and crosstalk exists with the PAP-mediated retrograde signalling pathway. The export mechanisms of MgProtoIX(/-ME) and MEcPP are unknown, but the latter may move directly to the endoplasmic reticulum via MCSs. MgProtoIX(/-ME) interacts with an HSP90 chaperone complex in the cytosol which can regulate the promoter binding of TFs in the nucleus (including HY5 and PRR5, via ZTL) and influence the expression of nuclear-encoded chloroplast proteins including PhANGs. In response to stress, MEcPP activates the UPR in the endoplasmic reticulum by activating expression of UPR and stress genes (including bZIP60 and possibly HPL) via the TF CAMTA3 in a calcium-dependent manner. MEcPP may also regulate expression of the TF BBX19 and influence growth and development via an unknown mechanism; it may also induce chromatin remodelling, though this has not yet been observed in plants. The accumulation of PAP in mitochondria has not been observed despite the presence of the SAL1 enzyme. Proposed activities in the cell are indicated by dashed lines. ABA, abscisic acid; CAMTA3, HDS: 1-hydroxy-2-methyl-2-E)-butenyl-4-diphosphate synthase; MCS, membrane contact sites; MEcPP, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate; MgProtoIX(/-ME), magnesium protoporphyrin 9 (and its monomethylester derivative); PAP, 3ʹ-phosphoadenosine 5ʹ-phosphate; PhANGs, photosynthesis-associated nuclear genes; ROS, reactive oxygen species; TFs, transcription factors; UPR, unfolded protein response; XRNs, 5ʹ–3ʹ exoribonucleases. Fig. 2. View largeDownload slide Metabolite-mediated retrograde signalling pathways triggered by abiotic stress. Three major pathways discussed in the text are shown. Drought, wounding, and high light stress induce the generation of ROS in the chloroplast, primarily from the photosynthetic electron transport chain. ROS may alter the chloroplastic redox state by oxidative modifications, which can inhibit the activity of specific enzymes in biosynthetic pathways, including SAL1, HDS, and the Mg-protoporphyrin monomethylester aerobic cyclase (CHL27), resulting in the accumulation of intermediate metabolites, including PAP, MEcPP, and MgProtoIX (/-ME). PAP is exported to the cytosol by the bidirectional transporter PAPST1 and may accumulate in the nucleus where it inhibits the activity of XRNs, altering RNA splicing and processing; PAP may also regulate the expression of stress response genes and calcium signalling components via unknown factors. Drought stress induces ABA signalling, which interacts with calcium signalling to regulate stomatal closure via the SLAC1 anion channel, and crosstalk exists with the PAP-mediated retrograde signalling pathway. The export mechanisms of MgProtoIX(/-ME) and MEcPP are unknown, but the latter may move directly to the endoplasmic reticulum via MCSs. MgProtoIX(/-ME) interacts with an HSP90 chaperone complex in the cytosol which can regulate the promoter binding of TFs in the nucleus (including HY5 and PRR5, via ZTL) and influence the expression of nuclear-encoded chloroplast proteins including PhANGs. In response to stress, MEcPP activates the UPR in the endoplasmic reticulum by activating expression of UPR and stress genes (including bZIP60 and possibly HPL) via the TF CAMTA3 in a calcium-dependent manner. MEcPP may also regulate expression of the TF BBX19 and influence growth and development via an unknown mechanism; it may also induce chromatin remodelling, though this has not yet been observed in plants. The accumulation of PAP in mitochondria has not been observed despite the presence of the SAL1 enzyme. Proposed activities in the cell are indicated by dashed lines. ABA, abscisic acid; CAMTA3, HDS: 1-hydroxy-2-methyl-2-E)-butenyl-4-diphosphate synthase; MCS, membrane contact sites; MEcPP, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate; MgProtoIX(/-ME), magnesium protoporphyrin 9 (and its monomethylester derivative); PAP, 3ʹ-phosphoadenosine 5ʹ-phosphate; PhANGs, photosynthesis-associated nuclear genes; ROS, reactive oxygen species; TFs, transcription factors; UPR, unfolded protein response; XRNs, 5ʹ–3ʹ exoribonucleases. There are two main theories regarding the molecular mechanism underlying MEcPP-mediated regulation of transcription. The first theory involves chromatin modifications and direct alteration of functional domains in the nucleus. MEcPP has been shown to disrupt interactions between DNA and a histone H1-like protein, resulting in de-condensation of nucleoids in the bacterial parasite Chlamydia trachomatis (Grieshaber et al., 2004). However, this has yet to be observed in plants. The second theory suggests a more direct means of MEcPP signal integration, at least for the ER–UPR signalling. Recent evidence indicates that this metabolite regulates the crosstalk between the JA and salicylic acid (SA) signalling pathways, which may modulate specific responses within the cell, including independent organelle-specific regulation of JA biosynthesis and degradation, and modulation of SA metabolism (Lemos et al., 2016; Bjornson et al., 2017). Glutathione redox balance was also affected, and this may underlie the generalized oxidative stress response and the multitude of stress signalling pathways which seem to be affected by MEcPP accumulation. These results suggest a role for MEcPP not only in plastid to nucleus communication but also in interorganellar communication in response to biotic and abiotic stress conditions. Indeed, membrane contact sites (MCS), which are sites of physical contact between the ER and the outer envelope of the chloroplast, may provide a route for direct export of MEcPP from the chloroplast and direct activation of UPR signalling in the ER itself (Andersson et al., 2007; Benn et al., 2016). Drought stress and PAP-mediated retrograde signalling Drought and salinity are significant abiotic stress factors which limit the distribution and productivity of plants, causing serious agricultural losses (Agarwal et al., 2013; Golldack et al., 2014). Under drought conditions, photosynthesis and energy metabolism are directly affected, as the stomatal closure to prevent water loss limits the diffusion of CO2 into the mesophyll cells (Chaves et al., 2009; Golldack et al., 2014). Plants can adapt to these conditions by a global re-programming of primary metabolism and alteration of cellular architecture. A novel mechanism has recently been elucidated which implicates the metabolite 3ʹ-phosphoadenosine 5ʹ-phosphate (PAP) as a second messenger, mediating a chloroplast signal in response to oxidative stress caused by drought and high light. PAP is a metabolite found in every known organism, and is formed as a by-product of secondary sulphur metabolism. PAP is the primary in vivo substrate of the enzyme SAL1 (inositol polyphosphate 1-phosphatase), which is found in chloroplasts and mitochondria, and catalyses the dephosphorylation of PAP to AMP (Estavillo et al., 2011). The alx8 (altered expression of APX2) mutant of Arabidopsis, which contains a lesion in the SAL1 gene, displays constitutively altered expression of >1800 transcripts (including up to 25% of all high light- and stress-responsive genes) and increased drought tolerance (Wilson et al., 2009; Estavillo et al., 2011). Silencing of the SAL1 homologue in wheat (Triticum aestivum) also demonstrated an increased drought tolerance, suggesting that the role of this enzyme is conserved through the plant kingdom (Manmathan et al., 2013). The recent elucidation of the crystal structure of the dimeric SAL1 protein revealed intra- and intermolecular disulphide bridges, which suggested a mechanism by which this enzyme may respond to the redox state within the chloroplast and thereby activate the PAP-mediated pathway in response to oxidative stress (Chan et al., 2016a). Increased ROS generation due to drought or high light inhibits the activity of SAL1 via oxidation of the disulphide bridges and subsequent dimerization, as well as glutathionylation of redox-sensitive cysteine residues (Chan et al., 2016a) (Fig. 2). This inhibition of SAL1 by oxidative stress increases the accumulation of PAP, which can move to the nucleus via the bidirectional transporter PAPST1 and thus act as a second messenger, influencing the expression of abiotic stress response proteins such as EARLY LIGHT-INDUCED PROTEIN2 (ELIP2) and ascorbate peroxidase 2 (APX2) (Estavillo et al., 2011; Gigolashvili et al., 2012). PAP inhibits the 5ʹ–3ʹ exoribonucleases (XRNs) in the nucleus and thereby alters the RNA processing. However, the exact mechanism of XRN-mediated RNA processing, and how it is regulated in response to PAP accumulation, is unknown. The RNA degradation activities of the yeast XRN homologues are inhibited by PAP accumulation, and the Arabidopsis xrn2xrn3 double mutant phenocopies alx8, which suggests that this mechanism is conserved (Dichtl et al., 1997; Estavillo et al., 2011). A proteomic analysis of tomato chloroplasts during drought and subsequent recovery revealed that a specific, PAP-mediated pathway moderates chloroplast acclimation and adaptation to water deficit. It was hypothesized that at some point in the signalling pathway, this PAP-mediated signal was integrated with abscisic acid (ABA) signalling to induce the appropriate transcriptional response (Tamburino et al., 2017). Indeed, it was recently observed that the SAL1–PAP–XRN oxidative stress signalling system interacts with ABA signalling in Arabidopsis guard cells to regulate slow anion channel associated 1 (SLAC1)-mediated stomatal closure and drought-responsive gene expression, via an alternative pathway independent of the canonical ABA signalling components OST1 and ABA-insensitive 1 (ABI1) (Fig. 2) (Geiger et al., 2009; Pornsiriwong et al., 2017). In the latter report it was suggested that PAP could act as an agonist of the ABA signalling pathway through its XRN inhibition activity, and that the PAP–XRN signalling pathway also interacted with ROS and Ca2+ signalling components, including the calcineurin B-like protein (CBL)–CBL-interacting protein kinase (CIPK) modules and calcium-dependent protein kinases (CDPKs) (Pornsiriwong et al., 2017). In addition, PAP-mediated signals may converge with mitochondrial RS pathways mediated by the TF ANAC017 to regulate PCD in response to organelle failure under stress conditions. However, while SAL1 is found in mitochondria, the role of PAP in mitochondrial RS is still unclear (Van Aken and Whelan, 2012; Ng et al., 2013b; Van Aken and Pogson, 2017). Signals from dysfunctional mitochondria The mitochondria and chloroplast depend upon each other for exchange of metabolites and energy equivalents. Photosynthesis provides substrates for mitochondrial respiration, and transporters located in the envelope membranes of mitochondria and chloroplasts mediate the exchange of metabolites, which constitutes an important channel of communication between the organelles. In addition, mitochondria act as a sink for excess reducing equivalents under stress conditions, and mitochondrial respiration is crucial for plant survival during drought and the concomitant collapse of photosynthesis (Yoshida et al., 2007; Atkin and Macherel, 2009). Similar to the chloroplast, most mitochondrial proteins are nuclear encoded, and mitochondrial RS is also necessary for proper function. Several studies indicate that mitochondrial RS in plant cells is triggered by stress or dysfunction in a similar manner to what has been described for chloroplasts such as disruption of the ETC or the tricarboxylic acid (TCA) cycle, and the gene expression may be altered in a very similar manner by chloroplastic and mitochondrial retrograde signals (Van Aken and Whelan, 2012). A meta-analysis of transcriptome changes resulting from mitochondrial impairment identified three main functional categories which are robustly regulated by mitochondrial RS: protein synthesis, plant–pathogen interactions, and the light reactions of photosynthesis. It was also suggested that mitochondrial RS exerts its effects through regulation not only of gene expression but also of translational activity (Schwarzländer et al., 2012). A well-described target of mitochondrial RS is the nuclear gene encoding ALTERNATIVE OXIDASE1 (AOX1). This terminal oxidase, localized to the inner mitochondrial membrane, couples the oxidation of ubiquinone to the reduction of O2 without the generation of a proton motive force or ATP. This confers an alternative electron transport pathway in mitochondria, and can minimize or regulate ROS generation and oxidative stress (Vanlerberghe, 2013; Ng et al., 2014). Several recent reports indicated that AOX activity is required for optimum respiration in the light, which in turn affects energy balance in the chloroplast (NADPH/NADP+ ratio) and the PSII excitation pressure, especially during light and drought stress (Dahal et al., 2016; Zhang et al., 2016). The TF ABI4 has been shown to regulate the expression of both AOX1a and PhANG genes in response to mitochondrial and plastid retrograde signals, respectively (Koussevitzky et al., 2007; Giraud et al., 2009; Blanco et al., 2014; Chan et al., 2016b; Dahal et al., 2016). Integration of energy and retrograde signalling pathways The regulator of alternative oxidase1 (rao1) mutants were identified in a forward genetics screen of mutagenized Arabidopsis plants unable to induce AOX1a expression in response to inhibitors of mitochondrial activity (antimycin A, myxothiazol, and monofluoroacetate), as well as general oxidative stress (H2O2) and abiotic stress (cold) (Ng et al., 2013a). The RAO1 gene encodes the CYCLIN DEPENDENT KINASE E1/CDK8/HUA ENHANCER 3 (HEN3) protein (CDKE1). CDKE1 is the catalytic subunit of the cyclin kinase module (CKM) of the Mediator transcriptional co-activator complex (Bourbon, 2008; Ng et al., 2013a). The multiprotein Mediator complex is an evolutionarily conserved co-regulator complex, essential for RNA polymerase II (RNAP II)-dependent transcription in eukaryotes (Yang et al., 2016). In plants, the Mediator complex has been biochemically purified from Arabidopsis and rice, and genetically characterized in many other species, including rice, wheat, soybean, corn, and the moss Physcomitrella patens, and it appears to be highly conserved across the plant kingdom. Mediator consists of anywhere between 25 and 35 subunits organized into four major modules, the head, middle, tail, and the CDKE1-containing kinase modules. However, the exact structure of the complex, and the localization and function of many subunits, including some plant-specific subunits, remains unsolved (Bäckström et al., 2007; Bourbon, 2008; Mathur et al., 2011; Yang et al., 2016; Samanta and Thakur, 2017). CDKE1 was classified as an E-type CDK with a SPTAIRE cyclin-binding motif in the kinase domain (Joubès et al., 2000). These kinases are known to regulate cell division and differentiation, and the cdke1/hen3 mutant of Arabidopsis also displays defects in floral organ identity (Wang and Chen, 2004). Genes encoding biotic and abiotic stress response proteins are over-represented in the differentially regulated transcripts in the rao1 plants, including protein and MAPK kinases, transmembrane receptor proteins, and mitochondrial stress-related components (Van Aken et al., 2009; Ng et al., 2013a). Interestingly, a light-sensitive phenotype was observed for rao1 plants following a shift from low to high light, along with an inability to recover both PSII and PSI activity following high light exposure. In addition, both AOX1a and LHCB2.4 were misregulated in response to photosynthetic ETC inhibitors and high light (Blanco et al., 2014). This suggests a role for CDKE1/RAO1 in the perception of retrograde signals from not only mitochondria, but also chloroplasts in response to redox changes (Fig. 3). Given the position of CDKE1 in the Mediator complex, it was suggested that this kinase could act as a sensitive relay between organellar retrograde signals and/or their cognate promoter-bound, stress-induced TFs and RNAP II, regulating the expression of appropriate genes in response to stress conditions. Fig. 3. View largeDownload slide Integration of retrograde signalling and energy-related pathways by the Mediator complex. Photosynthesis in the chloroplast, and respiration and oxidative phosphorylation in the mitochondria synthesize and degrade sugars, respectively, and influence sugar and energy signalling. Sugar/energy and stress signalling converge on KIN10, the catalytic subunit of the probable trimeric SNF1-related protein kinase (SnRK) complex. KIN10 may shuttle between the cytoplasm and the nucleus, where it interacts with CDKE1 (RAO1/HEN3). CDKE1 is a subunit of the cyclin kinase module of the Mediator complex, a conserved transcriptional co-activator, which integrates regulatory signals from many pathways, regulates chromatin and higher order genome structure, and induces activation of transcription by RNAP II. Depending on the environmental conditions and signals received, CDKE1 may influence the transition between transcription of genes associated with growth and development (such as PhANGs, protein synthesis, and central metabolism) or stress responses (mitochondrial stress genes such as AOX1a, and starvation response genes such as DIN1 and DIN6). Other Mediator subunits, including MED16 and MED14 of the tail and middle modules, respectively, interact with DNA-bound TFs to regulate the transcription of abiotic stress response genes such as the COR genes for cold acclimation. The shuttling of KIN10 between the cytoplasm and nucleus has been observed in yeast but not yet in plants. AOX1a, alternative oxidase 1a; CDKE1, cyclin-dependent kinase 1; COR, cold-regulated; DIN, dark-induced; KIN10, sucrose non-fermenting related kinase 1 (SnRK1) catalytic subunit; PhANGs, photosynthesis-associated nuclear genes; RNAP II, RNA polymerase II; RS, retrograde signalling; TFs, transcription factors. Fig. 3. View largeDownload slide Integration of retrograde signalling and energy-related pathways by the Mediator complex. Photosynthesis in the chloroplast, and respiration and oxidative phosphorylation in the mitochondria synthesize and degrade sugars, respectively, and influence sugar and energy signalling. Sugar/energy and stress signalling converge on KIN10, the catalytic subunit of the probable trimeric SNF1-related protein kinase (SnRK) complex. KIN10 may shuttle between the cytoplasm and the nucleus, where it interacts with CDKE1 (RAO1/HEN3). CDKE1 is a subunit of the cyclin kinase module of the Mediator complex, a conserved transcriptional co-activator, which integrates regulatory signals from many pathways, regulates chromatin and higher order genome structure, and induces activation of transcription by RNAP II. Depending on the environmental conditions and signals received, CDKE1 may influence the transition between transcription of genes associated with growth and development (such as PhANGs, protein synthesis, and central metabolism) or stress responses (mitochondrial stress genes such as AOX1a, and starvation response genes such as DIN1 and DIN6). Other Mediator subunits, including MED16 and MED14 of the tail and middle modules, respectively, interact with DNA-bound TFs to regulate the transcription of abiotic stress response genes such as the COR genes for cold acclimation. The shuttling of KIN10 between the cytoplasm and nucleus has been observed in yeast but not yet in plants. AOX1a, alternative oxidase 1a; CDKE1, cyclin-dependent kinase 1; COR, cold-regulated; DIN, dark-induced; KIN10, sucrose non-fermenting related kinase 1 (SnRK1) catalytic subunit; PhANGs, photosynthesis-associated nuclear genes; RNAP II, RNA polymerase II; RS, retrograde signalling; TFs, transcription factors. The impaired ability of rao1/cdke1 mutant plants to integrate signals originating in the different organelles emphasizes the importance of maintaining cellular energy homeostasis. Genes associated with energy signalling and central metabolism components were misregulated in rao1 plants, energy stress markers such as DIN6 (dark-inducible 6) were up-regulated, while genes encoding protein synthesis and metabolism components were down-regulated, which implicates CDKE1 as a central determinant of the transition between growth and stress response states (Fig. 3) (Baena-González et al., 2007; Ng et al., 2013a). Using bimolecular fluorescent complementation (BiFC) in onion epidermal cells, CDKE1 was shown to interact with the Snf1-related kinase 1 (SnRK1) kinase KIN10, an integrator of various stress responses and energy signalling (Baena-González et al., 2007; Ng et al., 2013a). KIN10 is the Arabidopsis catalytic subunit of SnRK1, a highly conserved central regulator of energy metabolism in eukaryotes, and is mainly active under low energy conditions to repress growth (Baena-González et al., 2007; Lastdrager et al., 2014). This interaction takes place in the nucleus, although KIN10 target sites have been identified in both the nucleus and cytosol (Baena-González et al., 2007), suggesting that KIN10 may serve as a signal carrier to CDKE1 in the nucleus (Fig. 3). Interestingly, several chloroplast proteins were also recently identified as putative targets of SnRK1 (Nukarinen et al., 2016). The moss (P. patens) snrk1a snrk1b double mutant is viable but displays complex developmental and energy metabolism phenotypes, including a requirement for constant light (Thelander et al., 2004). The Saccharomyces cerevisiae homologue of the KIN10/SnRK1 kinase, Snf1, has been shown to interact with CKM subunits of the yeast Mediator complex in response to sugar signals (Kuchin et al., 2000). Thus, this conserved KIN10–CDKE1 sensor–activator couple may integrate energy and retrograde signals, and regulate the redistribution of energy and metabolism towards either growth or stress response (Fig. 3). Role of the Mediator complex as a central regulatory hub CDKE was identified as a putative integrator of retrograde signals originating in chloroplasts and mitochondria. CDKE is a component of the Mediator complex that relays regulatory signals between specific transcription factors bound to the promoter and RNAP II (Yang et al., 2016) probably through large-scale changes in both composition and conformation (Allen and Taatjes, 2015). Due to this link between regulatory input and transcriptional output, Mediator is often thought of as an integration point for many signalling pathways in the nucleus. Mediator may also have a significant role in regulating higher order genome structure, including chromatin remodelling, chromosomal binding, actin assembly, DNA looping, and RNA metabolism (Carlsten et al., 2013; Chereji et al., 2017). Thus, Mediator is in a perfect setting to integrate signals regulating cellular energy metabolism in response to stress and changes in growth conditions. Analyses of mutants of individual Mediator subunits in Arabidopsis support an important role for the Mediator as a regulatory hub controlling transcriptional activity in response to plant stress responses. Many of the Mediator subunits have appeared in various genetic screens for mutants with impaired stress responses. For example, the MED16 subunit of the Mediator tail module is also known as SENSITIVE TO FREEZING 6 (SFR6) due to a failure in development of freezing tolerance and an inability to induce expression of the COLD REGULATED (COR) genes during cold acclimation (Fig. 3) (Knight et al., 2009; Wathugala et al., 2011; Hemsley et al., 2014). MED14 and MED2 were also shown to be involved in regulation of COR expression during cold acclimation, and both MED16 and MED14 participate in multiple pathways involved in plant immune responses (Zhang et al., 2013; Hemsley et al., 2014). In addition, biotic defence pathways including JA- and SA-mediated signalling, response to abiotic stresses such as high light, cold, drought, and salt, and control of metabolism homeostasis can be linked to the Mediator (reviewed in Yang et al., 2016; Dolan and Chapple, 2017). MED16/SFR6 has also been shown to participate in iron homeostasis and resistance to osmotic stress (Boyce et al., 2003; Yang et al., 2014). A plant-specific Mediator subunit, MED25/PHYTOCHROME AND FLOWERING TIME 1 (PFT1), has been implicated in a number of signalling pathways, including immune responses, light quality, flowering time, iron homeostasis, and ABA signalling (Çevik et al., 2012; Chen et al., 2012; Yang et al., 2014; Liu et al., 2016). In addition, the med25 mutant plants were salt sensitive but drought resistant (Elfving et al., 2011). The strong links described between the Mediator subunits and a wide range of plant stress responses support a putative role for Mediator as the final integration point for multiple, convergent signalling pathways controlling transcriptional output by RNAP II (Yang et al., 2016). Thus, Mediator is in a perfect setting to act as a regulatory hub integrating stress signals from both organelles and other cellular compartments, regulating cellular energy metabolism in response to stress and changes in growth conditions. Possibly the signals are perceived by the conserved KIN10–CDKE1 complex and transduced to the Mediator to initiate the transcriptional response (Fig. 3). However, the mechanism underlying a role for the Mediator as a regulatory hub and the specific involvement of CDKE1 are still unclear. Concluding remarks The organelles produce multiple signals in response to fluctuations in the environment that orchestrate major changes in nuclear gene expression. However, for the plant to respond optimally to environmental stress, information must be integrated from signals originating in different cellular compartments. A common feature following exposure to various stress conditions is an accumulation of ROS and, when environmental factors such as temperature or water availability constrain photosynthetic or respiratory electron transport, ROS accumulates in the organelles. ROS are themselves believed to act as RS molecules, but ROS also inhibits the activity of key enzymes in various biosynthetic pathways, resulting in the accumulation of specific metabolites such as PAP and MEcPP, which also act as signalling molecules in stress-triggered RS (Fig. 2). If and how the different retrograde signals triggered by the same type of stress, such as PAP and ROS, are integrated remains to be determined. In addition, it is necessary for the plant to perceive the signature of the ROS signal to trigger the correct change in gene expression. Identifying the mechanism by which the plant cell can recognize the cellular origin of a specific ROS signal and trigger the appropriate response will be a challenge for the future. It is clear that retrograde signals play an important role during plant stress responses, regulating a large number of genes in response to stress. Operational retrograde signals communicate impaired function of the power-houses of the plant cell, and a switch from growth to stress response is essential for the stress acclimation process. The Mediator complex appears to functions as a regulatory hub to integrate different stress- and energy-related signals, possibly through the kinase module, to control changes in gene expression required for the acclimation to stress (Fig. 3). Further research must address the role of this complex, address whether the individual subunits play specific roles in the stress responses, and determine the nature of signals perceived by Mediator. Abbreviations: Abbreviations: ABA abscisic acid ABI ABA-insensitive alx8 altered expression of APX2 AOX alternative oxidase BBX19 B-box protein 19 BiP binding immunoglobulin protein bZIP basic leucine zipper CAMTA3 CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR3 β-CC β-cyclocitral CDKE1/CDK8 cyclin-dependent kinase E1 ceh1 constitutively expressing hydroperoxyde lyase1 CKM cyclin kinase module of Mediator complex COR cold-regulated DIN6 dark-inducible 6 ER endoplasmic reticulum ETC electron transport chain EX1/EX2 EXECUTER 1/EXECUTER2 flu fluorescent in blue light GUN genomes uncoupled HDS 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase HEN3 HUA ENHANCER 3 H2O2 hydrogen peroxide HPL hydroperoxide lyase HSP heat shock protein HY5 LONG HYPOCOTYL 5 IRE1 INISITOL REQUIRING 1 JA jasmonic acid KIN10 Snf1 kinase homologue 10 MAPK mitogen-activated protein kinase MCS membrane contact site MEcPP 2-C-methyl-d-erythritol 2,4-cyclodiphosphate MED Mediator MgProtoIX Mg2+ protoporphyrin IX 1O2 singlet oxygen O2–· superoxide anion radical PAP 3ʹ-phosphoadenosine 5ʹ-phosphate PCD programmed cell death PhANG photosynthesis-associated nuclear gene PRR5 PSEUDO RESPONSE REGULATOR 5 rao1 regulator of alternative oxidase 1 RNAP II RNA polymerase II ROS reactive oxygen species RS retrograde signalling SA salicylic acid SFR6 SENSITIVE TO FREEZING 6 SnRK1 Snf1-related kinase 1 SORG 1O2-responsive gene TBP tetrapyrrole biosynthesis pathway TF transcription factor UPR unfolded protein response XRN 5ʹ–3ʹ exoribonucleases ZAT zinc finger transcription factor of Arabidopsis thaliana ZTL ZEITLUPE References Aarti PD, Tanaka R, Tanaka A. 2006. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Experimental Botany Oxford University Press

The role of retrograde signals during plant stress responses

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Oxford University Press
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© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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0022-0957
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10.1093/jxb/erx481
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Abstract

Abstract Chloroplast and mitochondria not only provide the energy to the plant cell but due to the sensitivity of organellar processes to perturbations caused by abiotic stress, they are also key cellular sensors of environmental fluctuations. Abiotic stresses result in reduced photosynthetic efficiency and thereby reduced energy supply for cellular processes. Thus, in order to acclimate to stress, plants must re-program gene expression and cellular metabolism to divert energy from growth and developmental processes to stress responses. To restore cellular energy homeostasis following exposure to stress, the activities of the organelles must be tightly co-ordinated with the transcriptional re-programming in the nucleus. Thus, communication between the organelles and the nucleus, so-called retrograde signalling, is essential to direct the energy use correctly during stress exposure. Stress-triggered retrograde signals are mediated by reactive oxygen species and metabolites including β-cyclocitral, MEcPP (2-C-methyl-d-erythritol 2,4-cyclodiphosphate), PAP (3ʹ-phosphoadenosine 5ʹ-phosphate), and intermediates of the tetrapyrrole biosynthesis pathway. However, for the plant cell to respond optimally to environmental stress, these stress-triggered retrograde signalling pathways must be integrated with the cytosolic stress signalling network. We hypothesize that the Mediator transcriptional co-activator complex may play a key role as a regulatory hub in the nucleus, integrating the complex stress signalling networks originating in different cellular compartments. Abiotic stress, energy metabolism, Mediator complex, photosynthesis, reactive oxygen species, retrograde signalling Introduction In the first half of the 21st century, the world’s population is predicted to surpass 9 billion, and the issue of obtaining food security for this massive population is becoming increasingly compounded by changes to our climate, constituting perhaps one of the greatest challenges our society has ever faced (Thornton et al., 2014). Plants are often exposed to unfavourable or stressful conditions in their growth environment, and have evolved sophisticated means by which they can survive and reproduce under abiotic stress conditions such as water deficit, high salt concentrations, and temperature extremes. Extreme growth conditions will become more common in the future as a result of changing land use and atmospheric composition (Fedoroff et al., 2010; Sterling et al., 2012). Thus, the natural evolutionary and plastic responses of plants upon which we are so dependent may not be enough to keep pace with the rapid rate of climate change (Franks et al., 2014). It is therefore crucial that we focus on elucidating the regulatory components and molecular mechanisms involved in acclimation and adaptation to stress conditions, as this knowledge will give rise to concrete biotechnological and agricultural advances for plant breeding and the engineering of plants with enhanced tolerance. Acclimation to stress conditions requires a metabolic and energetic investment, and this usually comes at the expense of energy available for growth and development (Baena-González, 2010). This review will focus on the role of organelles and retrograde signalling (RS) during the response to abiotic stress conditions, with emphasis on the recovery of cellular energy metabolism. Retrograde signals involved in operational control The organelles play critical roles as sensors of changes in the growth environment, and high crop yields are closely associated with the capacity to maintain photosynthesis and cellular metabolism during stress (Fernández and Strand, 2008). The chloroplasts and the mitochondria are the power-houses of the plant cell. Photosynthesis provides the energy, oxygen, and reduced carbon required for most life on our planet, yet the photosynthetic reactions housed in the chloroplasts are extremely sensitive to changes in the growth environment (Huner et al., 1998; Bode et al., 2016). Abiotic stress conditions cause photoinhibition of PSII and inhibition of the enzymes involved in carbon assimilation (Murata et al., 2007). In the mitochondria, aerobic respiration and oxidative phosphorylation provide ATP required for cellular functions, and these reactions are also highly sensitive to stress conditions. Exposure to abiotic stress results in a decrease in the overall efficiency of photosynthesis and respiration, and, as a consequence, cellular energy supply. Thus, it is essential for plants to restore their energy homeostasis via recovery of perturbed photosynthesis and respiration if they are to survive the stress. These responses require an adjustment of gene expression and metabolism towards defence and acclimation, which demands a distribution of energy away from biosynthetic growth and development processes (Baena-González, 2010). The progenitors of chloroplasts and mitochondria were thought to have once existed as free-living prokaryotic organisms, and were integrated into ancestral eukaryotic cells through endosymbiosis. During evolution, the functional control of these endosymbionts was acquired by the nucleus along with most of their genome. However, a small, independently replicating genome has been retained in each organelle, which encodes a small number of proteins required for organellar function (Dyall, 2004; Barajas-López et al., 2013). The activities of these genomes must be co-ordinated with gene expression in the nucleus to enable proper organellar function and energy metabolism, especially during stress exposure. This requires communication between the organelles and the nucleus, both anterograde (nucleus to organelle) and retrograde (organelle to nucleus) communication. Retrograde communication is a vital and continuous process throughout the life of the plant. The types of active signalling pathways and the responses are modulated according to the developmental and metabolic status of the plant. Retrograde signals can be divided into ‘biogenic’, referring to signals generated by the plastid as it develops from a proplastid or etioplast into a chloroplast, and ‘operational’ signals, including those generated from a mature chloroplast in response to environmental perturbations (Chan et al., 2016b). A recent meta-analysis of transcriptomes indicated that of the genes differentially regulated in response to abiotic stress, between 10% and 20% encode proteins localized to the chloroplasts, emphasizing the important role of these organelles during plant stress responses (Kmiecik et al., 2016). In this review, we will focus on the role of the operational retrograde signals in mediating the transcriptional response to abiotic stress conditions. Reactive oxygen species (ROS), a source of oxidative stress and second messengers Following exposure to various stress conditions, accumulation of ROS is very common. These oxygen derivatives have an increasingly appreciated dual role: as unwanted by-products of cellular metabolism they interact with and can destroy functional proteins, lipids, and metabolites through oxidative degradation, yet evolution has harnessed ROS as essential messengers in signal transduction (Schmitt et al., 2014; Mignolet-Spruyt et al., 2016). Production or transfer of reducing equivalents or electrons during photosynthesis and respiration inevitably generates ROS in the chloroplast, mitochondria and peroxisomes, and ROS generation increases during stress conditions due to suboptimal function of the components of the electron transport chains (ETCs) (Møller and Sweetlove, 2010; Cruz de Carvalho, 2008). ROS can transduce information from the organelles regarding the activity and redox state of the photosynthetic and respiratory ETCs, and integrate with and initiate signalling pathways in response to abiotic and biotic fluctuations in the environment (Barajas-López et al., 2013; Huang et al., 2016). ROS with known signalling functions include singlet oxygen (1O2), superoxide anion radical (O2–·), and hydrogen peroxide (H2O2) (Laloi et al., 2004; Corpas et al., 2017). Efficient photosynthesis depends on a tightly regulated balance between utilization and dissipation of light energy, and between the rates of damage and repair of the PSII complex (Takahashi and Murata, 2008). Transfer of excitation energy from triplet chlorophylls (such as the P680 reaction centre chlorophylls in PSII) to molecular oxygen causes the generation of singlet oxygen and photo-oxidative damage to the oxygen-evolving complex (OEC) and the D2 and particularly D1 subunits of PSII (Murata et al., 2007; Kale et al., 2017). PSII is one of the main sites of 1O2 generation in the cell and the initiation point of a signalling cascade (Fig. 1). Abiotic stresses can also cause inhibition of the highly efficient PSII repair pathway by inactivation of the translational machinery (which prevents the synthesis of replacement D1 polypeptides), as the thioredoxin-regulated translation factor EF-G required for D1 synthesis is specifically inhibited by H2O2 (Kojima et al., 2007; Takahashi and Murata, 2008; Nishiyama et al., 2011). In the chloroplast, H2O2 is generated via enzymatic dismutation of O2–· or reduction by plastoquinol (PQH2), the reduced form of plastoquinone (PQ), which also functions as an antioxidant while its oxidized form serves as an electron carrier upstream of the cytochrome b6f complex (Dietz et al., 2016) (Fig. 1). H2O2 may antagonize 1O2 signalling by maintaining QA (the primary electron acceptor quinone of PSII) in an oxidized state, thus keeping P680-mediated 1O2 generation at a low level (reviewed in Barajas-López et al., 2013). H2O2 is also formed as a by-product of metabolism in the peroxisomes, such as photorespiration by glycolate oxidase (GOX) or fatty acid β-oxidation through ATP-binding cassette (ABC) transporters and acetyl-CoA (Corpas et al., 2017). Superoxide radicals are generated at the acceptor side of illuminated PSI via the Mehler reaction, and the generation increases during carbon limitation or inhibition of Rubisco (Takahashi and Murata, 2008). Inhibition of Rubisco and limitation of carbon fixation are exacerbated by cold, heat, and salt stress, resulting in accumulation of reduced electron carriers at the acceptor side of PSI, such as NADPH. These electrons may be transferred to molecular oxygen, resulting in an increase in the generation of O2–· and thus H2O2 (via dismutation), which further increases PSII photoinhibition (Takahashi and Murata, 2008; Takahashi and Badger, 2011; Nishiyama and Murata, 2014) (Fig. 1). Fig. 1. View largeDownload slide Sites of ROS production in the chloroplast and the associated stress responses. The photosynthetic electron transport chain is one of the main sources of ROS, especially under stress conditions. Red arrows indicate abiotic stress-induced changes related to the photosynthetic apparatus. Singlet oxygen (1O2) from PSII, can be quenched by β-carotene (β-car) and through the non-enzymatic cleavage of β-car forming β-cyclocitral (β-CC) which, through the mediation of MBS1, acts as a secondary messenger and influences 1O2-responsive gene (SORG) expression. Alternatively the 1O2 signaling pathway is activated by EXECUTER1/EXECUTER2 (EX1/EX2). The two, most probably independent, pathways are physically separated within the grana: while the β-CC pathway takes place in the grana core, EX1 and EX2 are found in the margin regions of the grana. 1O2 is transformed into the less harmful hydrogen peroxide (H2O2) through the superoxide radical (O2–·). H2O2 also originates directly from plastoquinol (PQH2) and the cytochrome b6f complex (cyt b6f), while PSI is responsible for O2–· production, which can lead to H2O2 formation or programmed cell death (PCD). H2O2 is able to cross membranes through specific channels, called peroxiporins. Fig. 1. View largeDownload slide Sites of ROS production in the chloroplast and the associated stress responses. The photosynthetic electron transport chain is one of the main sources of ROS, especially under stress conditions. Red arrows indicate abiotic stress-induced changes related to the photosynthetic apparatus. Singlet oxygen (1O2) from PSII, can be quenched by β-carotene (β-car) and through the non-enzymatic cleavage of β-car forming β-cyclocitral (β-CC) which, through the mediation of MBS1, acts as a secondary messenger and influences 1O2-responsive gene (SORG) expression. Alternatively the 1O2 signaling pathway is activated by EXECUTER1/EXECUTER2 (EX1/EX2). The two, most probably independent, pathways are physically separated within the grana: while the β-CC pathway takes place in the grana core, EX1 and EX2 are found in the margin regions of the grana. 1O2 is transformed into the less harmful hydrogen peroxide (H2O2) through the superoxide radical (O2–·). H2O2 also originates directly from plastoquinol (PQH2) and the cytochrome b6f complex (cyt b6f), while PSI is responsible for O2–· production, which can lead to H2O2 formation or programmed cell death (PCD). H2O2 is able to cross membranes through specific channels, called peroxiporins. ROS transduction, recognition, and transcriptional responses Different ROS have different lifetimes and activities, and can trigger specific and generic responses depending on the compartment in which they are generated and the cellular environment with which they interact. Steady-state cellular ROS levels are under strict regulation by a dynamic and redundant network of ~152 genes in Arabidopsis, including ROS-generating and -scavenging enzymes (Mittler et al., 2004; Gechev et al., 2006). In plants with compromised levels of ROS-scavenging enzymes, or plants that were treated with ROS-generating agents, transcriptome analyses revealed unique source-specific groups of genes responding to the different treatments (Mittler et al., 2004; Gadjev et al., 2006; Møller and Sweetlove, 2010). This ROS identity-specific gene expression response was also confirmed by Affymetrix gene chip data, differentiating three clusters within 1206 differentially expressed genes; where 70 genes proved to be exclusively 1O2 responsive (cluster I), 9 genes responsive only to H2O2 (cluster II), and 31 genes responsive to both (cluster III) (op den Camp et al., 2003). The specific cellular response to ROS-mediated signalling depends on several factors: the type, dose, timing, and duration of the ROS signal and the site of the ROS generation (Gechev et al., 2006). Although various studies revealed that high doses of O2–· and H2O2 can trigger programmed cell death (PCD), while low doses generate acclimation responses against oxidative and abiotic stress, little is known about how specific ROS signals are perceived and how the appropriate transcriptional response is induced (Gechev et al., 2002; Vranová et al., 2002). It is thought that abiotic stresses, including drought, salinity, heat, and high light, produce distinctive global ROS signatures which can be perceived by appropriate receptors to induce the response required for the particular stress (Choudhury et al., 2016). Indeed, certain TFs are able to respond specifically to one type of ROS, but may also be influenced by the global ROS environment (Gadjev et al., 2006). H2O2 is able to cross biological membranes and migrate from its production site, most probably through H2O2-specific aquaporin channels, called peroxiporins (Henzler and Steudle, 2000; Bienert et al., 2006; Tian et al., 2016) (Fig. 1). In the nucleus, known targets of the H2O2-specific signalling pathway include metabolism- and immune response-related genes, such as cytochrome P450, PAL1, and GST6, and TFs including DEHYDRATION RESPONSIVE ELEMENT BINDING 2A (DREB2A), zinc finger transcription factor of Arabidopsis thaliana 12 (ZAT12), and members of the WRKY, basic helix–loop–helix (bHLH), heat shock protein (HSP), and mitogen-activated protein kinase (MAPK) cascade families (reviewed in Gadjev et al., 2006). Multiple lines of evidence suggest that H2O2-induced transcriptional responses occur in two stages: first, a quick activation of specific TFs such as ZAT12, followed by the induction of many downstream target genes in order to reach induction of full stress tolerance. The 1O2-responsive genes represent the largest single type of ROS-induced group (Gadjev et al., 2006). A specific function for 1O2 was discovered using the conditional flu (fluorescent in blue light) mutant of Arabidopsis, which contains a lesion in a regulatory protein of the tetrapyrrole biosynthesis pathway (TBP) and accumulates the intermediate protochlorophyllide in the dark. Upon transition of the flu mutant to light, a burst of 1O2 occurs which activates the expression of nuclear-encoded genes, many of which are involved in the stress acclimation response and PCD (Meskauskiene et al., 2001; Danon et al., 2005; Wang et al., 2016). Mor et al. (2014) also showed, using bioinformatic tools, that the transcriptomes of many stresses are correlated with the transcriptome described for the 1O2-producing flu mutant, suggesting that 1O2 is a common factor in many stress-induced signalling pathways. Due to its very short half-life (~200 ns) and strong reactivity, 1O2 itself is unlikely to be the retrograde signal; however, 1O2 may induce the generation of second messengers by oxidative modification of lipids, proteins, or pigments (Schmitt et al., 2014). To date, two 1O2-triggered signalling pathways have been revealed which transmit source-specific signals between the chloroplast and the nucleus (Møller and Sweetlove, 2010; Cruz de Carvalho, 2014). Carotenoid pigments such as β-carotene function as quenchers of 1O2 within the photosynthetic reaction centres and antennae (Triantaphylidés et al., 2008; Ramel et al., 2012a; Staleva et al., 2015). Non-enzymatic cleavage of β-carotene by 1O2 forms the volatile β-cyclocitral (β-CC) which, through the mediation with the downstream METHYLENE BLUE SENSITIVITY 1 (MBS1) protein (Shao et al., 2013; Shumbe et al., 2017), can act as a second messenger, influencing the expression of a set of 1O2-responsive genes (SORGs) (Ramel et al., 2012a, b) (Fig. 1). Another 1O2 signalling pathway requires the function of two nuclear-encoded and chloroplast-targeted proteins, EXECUTER1 (EX1) and EX2, to transfer the signal to the nucleus and regulate SORG expression. Inactivation of both EX1 and EX2 results in almost complete repression of SORGs (Wagner et al., 2004; Lee et al., 2007). It was recently shown that proteolysis of EX1 by the thylakoid metalloprotease FtsH2 is a critical early step in 1O2-triggered signalling (Wang et al., 2016). Interestingly, this process is spatially and functionally associated with the FtsH2-mediated PSII repair pathway, localized to the grana margins. In contrast, the β-CC-mediated 1O2 signalling pathway is initiated from the operational PSII reaction centres in the grana core (Bailey et al., 2002; Ramel et al., 2012b; Wang et al., 2016) (Fig. 1). Comparative analysis of transcripts regulated by these two separate mechanisms supports the existence of two independent signalling pathways, with only 20 genes in common (including WRKY33, WRKY40, and SIB1 TF genes) (Dogra et al., 2017). However, the reason for the co-existence of these two 1O2-triggered RS pathways, and whether they act truly independently from each other, remains to be elucidated. Tetrapyrrole biosynthesis and chloroplast retrograde signalling One of the plastid signals induced by oxidative stress is linked to tetrapyrrole biosynthesis, although the exact nature of this signal(s) has been debated for many years. Higher plants synthesize four major tetrapyrrole molecules—chlorophyll, haem, sirohaem, and phytochromobilin—via a common branched pathway in the plastids. While the biosynthetic pathway has common steps in the generation of early intermediates from the initial precursor glutamate, the flux through the Mg2+ (chlorophyll) and/or Fe2+ (haem and its linearized derivatives, bilins) branches of the pathway is carefully regulated at multiple levels (Kobayashi and Masuda, 2016). A tightly regulated synthesis is essential as many tetrapyrroles are excited by light and, if left unquenched, they can form highly toxic radicals. Changes to the flux through the TBP are indicators of developmental and environmental changes, and perturbations in the TBP have been shown to affect expression of photosynthesis-associated nuclear-encoded genes (PhANG genes) in both green algae and higher plants (Johanningmeier and Howell, 1984; Kropat et al., 1995, 1997, 2000; Strand et al., 2003; Alawady and Grimm, 2005; Pontier et al., 2007; von Gromoff et al., 2008; Zhang et al., 2011; Ibata et al., 2016). Arabidopsis mutants with impaired communication between the chloroplast and the nucleus, referred to as the gun (genomes uncoupled) mutants, were isolated from forward genetic screens (Susek et al., 1993; Mochizuki et al., 2001; Woodson et al., 2011). The gun mutants maintain expression of PhANG genes when exposed to oxidative stress, whereas wild-type plants demonstrate strong suppression of PhANG expression under the same conditions (Susek et al., 1993; Woodson et al., 2011). GUN2–GUN5 all encode components affecting the flux through the chlorophyll branch of the pathway, and the respective mutants all have a pale phenotype. GUN6, on the other hand, encodes ferrochelatase I of the haem biosynthesis pathway, and may induce an antagonistic signal to GUN2–GUN5 (von Gromoff et al., 2008; Woodson et al., 2011). Environmental changes affect the flux through the TBP, causing perturbations and accumulation of both ROS and specific intermediate metabolites, and mutants such as gun5 are more sensitive to abiotic stresses such as exposure to low temperatures (Kindgren et al., 2015). In particular, the aerobic cyclase reaction was shown, both in Arabidopsis and in cucumber, to be extremely sensitive to oxidative stress and ROS, resulting in the accumulation of upstream intermediates such as Mg protoporphyrin IX (MgProtoIX)/MgProtoIX-methylester (Aarti et al., 2006; Stenbaek et al., 2008) (Fig. 2). Accumulation of these intermediates was also observed in the crd mutant of Arabidopsis, which contains a mutation in the CHL27 gene encoding a putative cyclase subunit (Bang et al., 2008). These intermediates may leave the chloroplast by an unknown transporter, interact with and inhibit the ATPase activity of an HSP90 chaperone complex in the cytosol, and subsequently regulate expression of specific nuclear genes through regulation of the TFs LONG HYPOCOTYL5 (HY5) and PSEUDO RESPONSE REGULATOR 5 (PRR5) via ZEITLUPE (ZTL) (Fig. 2) (Kindgren et al., 2011, 2012; Norén et al., 2016). It was recently demonstrated that binding of ProtoIX to the GUN4 protein increased the production of 1O2, suggesting a connection between the tetrapyrrole-mediated signal and the EX1/EX2 proteins (Fig. 2) (Adhikari et al., 2009; Tarahi Tabrizi et al., 2016). Indeed, 1O2 generation from chlorophyll biosynthesis intermediates was recently proposed to initiate an EX1/EX2-mediated inhibitory retrograde signal, suppressing PhANG expression during seedling de-etiolation (Page et al., 2017). Furthermore, RNAi-mediated reduction of key enzymes in the chlorophyll biosynthesis pathway revealed a complex and time-dependent interplay between metabolite- and ROS-mediated RS processes (Schlicke et al., 2014). MEcPP-mediated retrograde signalling and ER stress Another plastid-derived signal mediated by a small metabolite is the 2-C-methyl-d-erythritol 2,4-cyclodiphosphate- (MEcPP) mediated signal, which has been confirmed as an operational retrograde signal produced in response to oxidative stress. A forward genetics approach identified the constitutively expressing hydroperoxide lyase1 (ceh1) mutant of Arabidopsis, which contains a lesion in the enzyme 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (HDS). This enzyme catalyses a rate-limiting reaction in the isoprenoid biosynthesis pathway, and ceh1 plants accumulate the intermediate MEcPP as a result (Fig. 2) (Xiao et al., 2012). Analyses of the transcriptome and proteome of ceh1 mutant plants indicated that MEcPP induced the expression of nuclear-encoded stress-responsive genes, including non-PhANG chloroplast-localized proteins and proteins involved in the response to endoplasmic reticulum (ER) stress (Xiao et al., 2012; Walley et al., 2015). The HDS enzyme contains a [4Fe–4S] cluster which makes it highly sensitive to oxidative stress, and accumulation of MEcPP has also been observed in wild-type plants in response to oxidative stress, high light, and wounding (Seemann et al., 2005). Furthermore, it was shown that MEcPP could act as a retrograde signal to induce the expression of nuclear genes encoding proteins involved in stress response and biotic defence signalling, including the plastid-localized hydroperoxide lyase (HPL) enzyme, involved in the biosynthesis of jasmonic acid (JA) (Xiao et al., 2012; de Souza et al., 2017) (Fig. 2). Overaccumulation of MEcPP in stressed wild-type or ceh1 plants was also suggested to result in reduced growth and early flowering, mediated via the B-box TF B-box protein 19 (BBX19) (Wang et al., 2015; de Souza et al., 2017). Two recent reports revealed that the MEcPP-mediated retrograde signal provides a mechanism for induction of the ER stress response. The accumulation of unfolded or misfolded proteins in the ER occurs as a consequence of exposure to both abiotic and biotic stress. The accumulation is sensed by sensor proteins as ER stress, and a series of sophisticated compensatory mechanisms called the unfolded protein response (UPR) is initiated (Liu and Howell, 2016). The UPR consists of an up-regulation of molecular chaperone and folding cofactors, 26S ubiquitin proteasome-mediated ER-associated degradation (ERAD), and suppression of protein translation. UPR is elicited by two pathways, one mediated by the ER-localized mRNA splicing factor INISITOL REQUIRING 1 (IRE1) and the TF basic leucine zipper 60 (bZIP60), and the another mediated by binding immunoglobulin proteins (BiPs) and the TFs bZIP28 and bZIP17 (Deng et al., 2011; Srivastava et al., 2013; reviewed in Bao and Howell, 2017). MEcPP was shown to activate the UPR by directly inducing the expression of bZIP60 and IRE1a, and bZIP28 and BiP3, via the nuclear TF CALMODULIN-BINDING TRASCRIPTIONAL ACTIVATOR 3 (CAMTA3) in a Ca2+-dependent manner (Fig. 2) (Walley et al., 2015; Benn et al., 2016). Fig. 2. View largeDownload slide Metabolite-mediated retrograde signalling pathways triggered by abiotic stress. Three major pathways discussed in the text are shown. Drought, wounding, and high light stress induce the generation of ROS in the chloroplast, primarily from the photosynthetic electron transport chain. ROS may alter the chloroplastic redox state by oxidative modifications, which can inhibit the activity of specific enzymes in biosynthetic pathways, including SAL1, HDS, and the Mg-protoporphyrin monomethylester aerobic cyclase (CHL27), resulting in the accumulation of intermediate metabolites, including PAP, MEcPP, and MgProtoIX (/-ME). PAP is exported to the cytosol by the bidirectional transporter PAPST1 and may accumulate in the nucleus where it inhibits the activity of XRNs, altering RNA splicing and processing; PAP may also regulate the expression of stress response genes and calcium signalling components via unknown factors. Drought stress induces ABA signalling, which interacts with calcium signalling to regulate stomatal closure via the SLAC1 anion channel, and crosstalk exists with the PAP-mediated retrograde signalling pathway. The export mechanisms of MgProtoIX(/-ME) and MEcPP are unknown, but the latter may move directly to the endoplasmic reticulum via MCSs. MgProtoIX(/-ME) interacts with an HSP90 chaperone complex in the cytosol which can regulate the promoter binding of TFs in the nucleus (including HY5 and PRR5, via ZTL) and influence the expression of nuclear-encoded chloroplast proteins including PhANGs. In response to stress, MEcPP activates the UPR in the endoplasmic reticulum by activating expression of UPR and stress genes (including bZIP60 and possibly HPL) via the TF CAMTA3 in a calcium-dependent manner. MEcPP may also regulate expression of the TF BBX19 and influence growth and development via an unknown mechanism; it may also induce chromatin remodelling, though this has not yet been observed in plants. The accumulation of PAP in mitochondria has not been observed despite the presence of the SAL1 enzyme. Proposed activities in the cell are indicated by dashed lines. ABA, abscisic acid; CAMTA3, HDS: 1-hydroxy-2-methyl-2-E)-butenyl-4-diphosphate synthase; MCS, membrane contact sites; MEcPP, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate; MgProtoIX(/-ME), magnesium protoporphyrin 9 (and its monomethylester derivative); PAP, 3ʹ-phosphoadenosine 5ʹ-phosphate; PhANGs, photosynthesis-associated nuclear genes; ROS, reactive oxygen species; TFs, transcription factors; UPR, unfolded protein response; XRNs, 5ʹ–3ʹ exoribonucleases. Fig. 2. View largeDownload slide Metabolite-mediated retrograde signalling pathways triggered by abiotic stress. Three major pathways discussed in the text are shown. Drought, wounding, and high light stress induce the generation of ROS in the chloroplast, primarily from the photosynthetic electron transport chain. ROS may alter the chloroplastic redox state by oxidative modifications, which can inhibit the activity of specific enzymes in biosynthetic pathways, including SAL1, HDS, and the Mg-protoporphyrin monomethylester aerobic cyclase (CHL27), resulting in the accumulation of intermediate metabolites, including PAP, MEcPP, and MgProtoIX (/-ME). PAP is exported to the cytosol by the bidirectional transporter PAPST1 and may accumulate in the nucleus where it inhibits the activity of XRNs, altering RNA splicing and processing; PAP may also regulate the expression of stress response genes and calcium signalling components via unknown factors. Drought stress induces ABA signalling, which interacts with calcium signalling to regulate stomatal closure via the SLAC1 anion channel, and crosstalk exists with the PAP-mediated retrograde signalling pathway. The export mechanisms of MgProtoIX(/-ME) and MEcPP are unknown, but the latter may move directly to the endoplasmic reticulum via MCSs. MgProtoIX(/-ME) interacts with an HSP90 chaperone complex in the cytosol which can regulate the promoter binding of TFs in the nucleus (including HY5 and PRR5, via ZTL) and influence the expression of nuclear-encoded chloroplast proteins including PhANGs. In response to stress, MEcPP activates the UPR in the endoplasmic reticulum by activating expression of UPR and stress genes (including bZIP60 and possibly HPL) via the TF CAMTA3 in a calcium-dependent manner. MEcPP may also regulate expression of the TF BBX19 and influence growth and development via an unknown mechanism; it may also induce chromatin remodelling, though this has not yet been observed in plants. The accumulation of PAP in mitochondria has not been observed despite the presence of the SAL1 enzyme. Proposed activities in the cell are indicated by dashed lines. ABA, abscisic acid; CAMTA3, HDS: 1-hydroxy-2-methyl-2-E)-butenyl-4-diphosphate synthase; MCS, membrane contact sites; MEcPP, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate; MgProtoIX(/-ME), magnesium protoporphyrin 9 (and its monomethylester derivative); PAP, 3ʹ-phosphoadenosine 5ʹ-phosphate; PhANGs, photosynthesis-associated nuclear genes; ROS, reactive oxygen species; TFs, transcription factors; UPR, unfolded protein response; XRNs, 5ʹ–3ʹ exoribonucleases. There are two main theories regarding the molecular mechanism underlying MEcPP-mediated regulation of transcription. The first theory involves chromatin modifications and direct alteration of functional domains in the nucleus. MEcPP has been shown to disrupt interactions between DNA and a histone H1-like protein, resulting in de-condensation of nucleoids in the bacterial parasite Chlamydia trachomatis (Grieshaber et al., 2004). However, this has yet to be observed in plants. The second theory suggests a more direct means of MEcPP signal integration, at least for the ER–UPR signalling. Recent evidence indicates that this metabolite regulates the crosstalk between the JA and salicylic acid (SA) signalling pathways, which may modulate specific responses within the cell, including independent organelle-specific regulation of JA biosynthesis and degradation, and modulation of SA metabolism (Lemos et al., 2016; Bjornson et al., 2017). Glutathione redox balance was also affected, and this may underlie the generalized oxidative stress response and the multitude of stress signalling pathways which seem to be affected by MEcPP accumulation. These results suggest a role for MEcPP not only in plastid to nucleus communication but also in interorganellar communication in response to biotic and abiotic stress conditions. Indeed, membrane contact sites (MCS), which are sites of physical contact between the ER and the outer envelope of the chloroplast, may provide a route for direct export of MEcPP from the chloroplast and direct activation of UPR signalling in the ER itself (Andersson et al., 2007; Benn et al., 2016). Drought stress and PAP-mediated retrograde signalling Drought and salinity are significant abiotic stress factors which limit the distribution and productivity of plants, causing serious agricultural losses (Agarwal et al., 2013; Golldack et al., 2014). Under drought conditions, photosynthesis and energy metabolism are directly affected, as the stomatal closure to prevent water loss limits the diffusion of CO2 into the mesophyll cells (Chaves et al., 2009; Golldack et al., 2014). Plants can adapt to these conditions by a global re-programming of primary metabolism and alteration of cellular architecture. A novel mechanism has recently been elucidated which implicates the metabolite 3ʹ-phosphoadenosine 5ʹ-phosphate (PAP) as a second messenger, mediating a chloroplast signal in response to oxidative stress caused by drought and high light. PAP is a metabolite found in every known organism, and is formed as a by-product of secondary sulphur metabolism. PAP is the primary in vivo substrate of the enzyme SAL1 (inositol polyphosphate 1-phosphatase), which is found in chloroplasts and mitochondria, and catalyses the dephosphorylation of PAP to AMP (Estavillo et al., 2011). The alx8 (altered expression of APX2) mutant of Arabidopsis, which contains a lesion in the SAL1 gene, displays constitutively altered expression of >1800 transcripts (including up to 25% of all high light- and stress-responsive genes) and increased drought tolerance (Wilson et al., 2009; Estavillo et al., 2011). Silencing of the SAL1 homologue in wheat (Triticum aestivum) also demonstrated an increased drought tolerance, suggesting that the role of this enzyme is conserved through the plant kingdom (Manmathan et al., 2013). The recent elucidation of the crystal structure of the dimeric SAL1 protein revealed intra- and intermolecular disulphide bridges, which suggested a mechanism by which this enzyme may respond to the redox state within the chloroplast and thereby activate the PAP-mediated pathway in response to oxidative stress (Chan et al., 2016a). Increased ROS generation due to drought or high light inhibits the activity of SAL1 via oxidation of the disulphide bridges and subsequent dimerization, as well as glutathionylation of redox-sensitive cysteine residues (Chan et al., 2016a) (Fig. 2). This inhibition of SAL1 by oxidative stress increases the accumulation of PAP, which can move to the nucleus via the bidirectional transporter PAPST1 and thus act as a second messenger, influencing the expression of abiotic stress response proteins such as EARLY LIGHT-INDUCED PROTEIN2 (ELIP2) and ascorbate peroxidase 2 (APX2) (Estavillo et al., 2011; Gigolashvili et al., 2012). PAP inhibits the 5ʹ–3ʹ exoribonucleases (XRNs) in the nucleus and thereby alters the RNA processing. However, the exact mechanism of XRN-mediated RNA processing, and how it is regulated in response to PAP accumulation, is unknown. The RNA degradation activities of the yeast XRN homologues are inhibited by PAP accumulation, and the Arabidopsis xrn2xrn3 double mutant phenocopies alx8, which suggests that this mechanism is conserved (Dichtl et al., 1997; Estavillo et al., 2011). A proteomic analysis of tomato chloroplasts during drought and subsequent recovery revealed that a specific, PAP-mediated pathway moderates chloroplast acclimation and adaptation to water deficit. It was hypothesized that at some point in the signalling pathway, this PAP-mediated signal was integrated with abscisic acid (ABA) signalling to induce the appropriate transcriptional response (Tamburino et al., 2017). Indeed, it was recently observed that the SAL1–PAP–XRN oxidative stress signalling system interacts with ABA signalling in Arabidopsis guard cells to regulate slow anion channel associated 1 (SLAC1)-mediated stomatal closure and drought-responsive gene expression, via an alternative pathway independent of the canonical ABA signalling components OST1 and ABA-insensitive 1 (ABI1) (Fig. 2) (Geiger et al., 2009; Pornsiriwong et al., 2017). In the latter report it was suggested that PAP could act as an agonist of the ABA signalling pathway through its XRN inhibition activity, and that the PAP–XRN signalling pathway also interacted with ROS and Ca2+ signalling components, including the calcineurin B-like protein (CBL)–CBL-interacting protein kinase (CIPK) modules and calcium-dependent protein kinases (CDPKs) (Pornsiriwong et al., 2017). In addition, PAP-mediated signals may converge with mitochondrial RS pathways mediated by the TF ANAC017 to regulate PCD in response to organelle failure under stress conditions. However, while SAL1 is found in mitochondria, the role of PAP in mitochondrial RS is still unclear (Van Aken and Whelan, 2012; Ng et al., 2013b; Van Aken and Pogson, 2017). Signals from dysfunctional mitochondria The mitochondria and chloroplast depend upon each other for exchange of metabolites and energy equivalents. Photosynthesis provides substrates for mitochondrial respiration, and transporters located in the envelope membranes of mitochondria and chloroplasts mediate the exchange of metabolites, which constitutes an important channel of communication between the organelles. In addition, mitochondria act as a sink for excess reducing equivalents under stress conditions, and mitochondrial respiration is crucial for plant survival during drought and the concomitant collapse of photosynthesis (Yoshida et al., 2007; Atkin and Macherel, 2009). Similar to the chloroplast, most mitochondrial proteins are nuclear encoded, and mitochondrial RS is also necessary for proper function. Several studies indicate that mitochondrial RS in plant cells is triggered by stress or dysfunction in a similar manner to what has been described for chloroplasts such as disruption of the ETC or the tricarboxylic acid (TCA) cycle, and the gene expression may be altered in a very similar manner by chloroplastic and mitochondrial retrograde signals (Van Aken and Whelan, 2012). A meta-analysis of transcriptome changes resulting from mitochondrial impairment identified three main functional categories which are robustly regulated by mitochondrial RS: protein synthesis, plant–pathogen interactions, and the light reactions of photosynthesis. It was also suggested that mitochondrial RS exerts its effects through regulation not only of gene expression but also of translational activity (Schwarzländer et al., 2012). A well-described target of mitochondrial RS is the nuclear gene encoding ALTERNATIVE OXIDASE1 (AOX1). This terminal oxidase, localized to the inner mitochondrial membrane, couples the oxidation of ubiquinone to the reduction of O2 without the generation of a proton motive force or ATP. This confers an alternative electron transport pathway in mitochondria, and can minimize or regulate ROS generation and oxidative stress (Vanlerberghe, 2013; Ng et al., 2014). Several recent reports indicated that AOX activity is required for optimum respiration in the light, which in turn affects energy balance in the chloroplast (NADPH/NADP+ ratio) and the PSII excitation pressure, especially during light and drought stress (Dahal et al., 2016; Zhang et al., 2016). The TF ABI4 has been shown to regulate the expression of both AOX1a and PhANG genes in response to mitochondrial and plastid retrograde signals, respectively (Koussevitzky et al., 2007; Giraud et al., 2009; Blanco et al., 2014; Chan et al., 2016b; Dahal et al., 2016). Integration of energy and retrograde signalling pathways The regulator of alternative oxidase1 (rao1) mutants were identified in a forward genetics screen of mutagenized Arabidopsis plants unable to induce AOX1a expression in response to inhibitors of mitochondrial activity (antimycin A, myxothiazol, and monofluoroacetate), as well as general oxidative stress (H2O2) and abiotic stress (cold) (Ng et al., 2013a). The RAO1 gene encodes the CYCLIN DEPENDENT KINASE E1/CDK8/HUA ENHANCER 3 (HEN3) protein (CDKE1). CDKE1 is the catalytic subunit of the cyclin kinase module (CKM) of the Mediator transcriptional co-activator complex (Bourbon, 2008; Ng et al., 2013a). The multiprotein Mediator complex is an evolutionarily conserved co-regulator complex, essential for RNA polymerase II (RNAP II)-dependent transcription in eukaryotes (Yang et al., 2016). In plants, the Mediator complex has been biochemically purified from Arabidopsis and rice, and genetically characterized in many other species, including rice, wheat, soybean, corn, and the moss Physcomitrella patens, and it appears to be highly conserved across the plant kingdom. Mediator consists of anywhere between 25 and 35 subunits organized into four major modules, the head, middle, tail, and the CDKE1-containing kinase modules. However, the exact structure of the complex, and the localization and function of many subunits, including some plant-specific subunits, remains unsolved (Bäckström et al., 2007; Bourbon, 2008; Mathur et al., 2011; Yang et al., 2016; Samanta and Thakur, 2017). CDKE1 was classified as an E-type CDK with a SPTAIRE cyclin-binding motif in the kinase domain (Joubès et al., 2000). These kinases are known to regulate cell division and differentiation, and the cdke1/hen3 mutant of Arabidopsis also displays defects in floral organ identity (Wang and Chen, 2004). Genes encoding biotic and abiotic stress response proteins are over-represented in the differentially regulated transcripts in the rao1 plants, including protein and MAPK kinases, transmembrane receptor proteins, and mitochondrial stress-related components (Van Aken et al., 2009; Ng et al., 2013a). Interestingly, a light-sensitive phenotype was observed for rao1 plants following a shift from low to high light, along with an inability to recover both PSII and PSI activity following high light exposure. In addition, both AOX1a and LHCB2.4 were misregulated in response to photosynthetic ETC inhibitors and high light (Blanco et al., 2014). This suggests a role for CDKE1/RAO1 in the perception of retrograde signals from not only mitochondria, but also chloroplasts in response to redox changes (Fig. 3). Given the position of CDKE1 in the Mediator complex, it was suggested that this kinase could act as a sensitive relay between organellar retrograde signals and/or their cognate promoter-bound, stress-induced TFs and RNAP II, regulating the expression of appropriate genes in response to stress conditions. Fig. 3. View largeDownload slide Integration of retrograde signalling and energy-related pathways by the Mediator complex. Photosynthesis in the chloroplast, and respiration and oxidative phosphorylation in the mitochondria synthesize and degrade sugars, respectively, and influence sugar and energy signalling. Sugar/energy and stress signalling converge on KIN10, the catalytic subunit of the probable trimeric SNF1-related protein kinase (SnRK) complex. KIN10 may shuttle between the cytoplasm and the nucleus, where it interacts with CDKE1 (RAO1/HEN3). CDKE1 is a subunit of the cyclin kinase module of the Mediator complex, a conserved transcriptional co-activator, which integrates regulatory signals from many pathways, regulates chromatin and higher order genome structure, and induces activation of transcription by RNAP II. Depending on the environmental conditions and signals received, CDKE1 may influence the transition between transcription of genes associated with growth and development (such as PhANGs, protein synthesis, and central metabolism) or stress responses (mitochondrial stress genes such as AOX1a, and starvation response genes such as DIN1 and DIN6). Other Mediator subunits, including MED16 and MED14 of the tail and middle modules, respectively, interact with DNA-bound TFs to regulate the transcription of abiotic stress response genes such as the COR genes for cold acclimation. The shuttling of KIN10 between the cytoplasm and nucleus has been observed in yeast but not yet in plants. AOX1a, alternative oxidase 1a; CDKE1, cyclin-dependent kinase 1; COR, cold-regulated; DIN, dark-induced; KIN10, sucrose non-fermenting related kinase 1 (SnRK1) catalytic subunit; PhANGs, photosynthesis-associated nuclear genes; RNAP II, RNA polymerase II; RS, retrograde signalling; TFs, transcription factors. Fig. 3. View largeDownload slide Integration of retrograde signalling and energy-related pathways by the Mediator complex. Photosynthesis in the chloroplast, and respiration and oxidative phosphorylation in the mitochondria synthesize and degrade sugars, respectively, and influence sugar and energy signalling. Sugar/energy and stress signalling converge on KIN10, the catalytic subunit of the probable trimeric SNF1-related protein kinase (SnRK) complex. KIN10 may shuttle between the cytoplasm and the nucleus, where it interacts with CDKE1 (RAO1/HEN3). CDKE1 is a subunit of the cyclin kinase module of the Mediator complex, a conserved transcriptional co-activator, which integrates regulatory signals from many pathways, regulates chromatin and higher order genome structure, and induces activation of transcription by RNAP II. Depending on the environmental conditions and signals received, CDKE1 may influence the transition between transcription of genes associated with growth and development (such as PhANGs, protein synthesis, and central metabolism) or stress responses (mitochondrial stress genes such as AOX1a, and starvation response genes such as DIN1 and DIN6). Other Mediator subunits, including MED16 and MED14 of the tail and middle modules, respectively, interact with DNA-bound TFs to regulate the transcription of abiotic stress response genes such as the COR genes for cold acclimation. The shuttling of KIN10 between the cytoplasm and nucleus has been observed in yeast but not yet in plants. AOX1a, alternative oxidase 1a; CDKE1, cyclin-dependent kinase 1; COR, cold-regulated; DIN, dark-induced; KIN10, sucrose non-fermenting related kinase 1 (SnRK1) catalytic subunit; PhANGs, photosynthesis-associated nuclear genes; RNAP II, RNA polymerase II; RS, retrograde signalling; TFs, transcription factors. The impaired ability of rao1/cdke1 mutant plants to integrate signals originating in the different organelles emphasizes the importance of maintaining cellular energy homeostasis. Genes associated with energy signalling and central metabolism components were misregulated in rao1 plants, energy stress markers such as DIN6 (dark-inducible 6) were up-regulated, while genes encoding protein synthesis and metabolism components were down-regulated, which implicates CDKE1 as a central determinant of the transition between growth and stress response states (Fig. 3) (Baena-González et al., 2007; Ng et al., 2013a). Using bimolecular fluorescent complementation (BiFC) in onion epidermal cells, CDKE1 was shown to interact with the Snf1-related kinase 1 (SnRK1) kinase KIN10, an integrator of various stress responses and energy signalling (Baena-González et al., 2007; Ng et al., 2013a). KIN10 is the Arabidopsis catalytic subunit of SnRK1, a highly conserved central regulator of energy metabolism in eukaryotes, and is mainly active under low energy conditions to repress growth (Baena-González et al., 2007; Lastdrager et al., 2014). This interaction takes place in the nucleus, although KIN10 target sites have been identified in both the nucleus and cytosol (Baena-González et al., 2007), suggesting that KIN10 may serve as a signal carrier to CDKE1 in the nucleus (Fig. 3). Interestingly, several chloroplast proteins were also recently identified as putative targets of SnRK1 (Nukarinen et al., 2016). The moss (P. patens) snrk1a snrk1b double mutant is viable but displays complex developmental and energy metabolism phenotypes, including a requirement for constant light (Thelander et al., 2004). The Saccharomyces cerevisiae homologue of the KIN10/SnRK1 kinase, Snf1, has been shown to interact with CKM subunits of the yeast Mediator complex in response to sugar signals (Kuchin et al., 2000). Thus, this conserved KIN10–CDKE1 sensor–activator couple may integrate energy and retrograde signals, and regulate the redistribution of energy and metabolism towards either growth or stress response (Fig. 3). Role of the Mediator complex as a central regulatory hub CDKE was identified as a putative integrator of retrograde signals originating in chloroplasts and mitochondria. CDKE is a component of the Mediator complex that relays regulatory signals between specific transcription factors bound to the promoter and RNAP II (Yang et al., 2016) probably through large-scale changes in both composition and conformation (Allen and Taatjes, 2015). Due to this link between regulatory input and transcriptional output, Mediator is often thought of as an integration point for many signalling pathways in the nucleus. Mediator may also have a significant role in regulating higher order genome structure, including chromatin remodelling, chromosomal binding, actin assembly, DNA looping, and RNA metabolism (Carlsten et al., 2013; Chereji et al., 2017). Thus, Mediator is in a perfect setting to integrate signals regulating cellular energy metabolism in response to stress and changes in growth conditions. Analyses of mutants of individual Mediator subunits in Arabidopsis support an important role for the Mediator as a regulatory hub controlling transcriptional activity in response to plant stress responses. Many of the Mediator subunits have appeared in various genetic screens for mutants with impaired stress responses. For example, the MED16 subunit of the Mediator tail module is also known as SENSITIVE TO FREEZING 6 (SFR6) due to a failure in development of freezing tolerance and an inability to induce expression of the COLD REGULATED (COR) genes during cold acclimation (Fig. 3) (Knight et al., 2009; Wathugala et al., 2011; Hemsley et al., 2014). MED14 and MED2 were also shown to be involved in regulation of COR expression during cold acclimation, and both MED16 and MED14 participate in multiple pathways involved in plant immune responses (Zhang et al., 2013; Hemsley et al., 2014). In addition, biotic defence pathways including JA- and SA-mediated signalling, response to abiotic stresses such as high light, cold, drought, and salt, and control of metabolism homeostasis can be linked to the Mediator (reviewed in Yang et al., 2016; Dolan and Chapple, 2017). MED16/SFR6 has also been shown to participate in iron homeostasis and resistance to osmotic stress (Boyce et al., 2003; Yang et al., 2014). A plant-specific Mediator subunit, MED25/PHYTOCHROME AND FLOWERING TIME 1 (PFT1), has been implicated in a number of signalling pathways, including immune responses, light quality, flowering time, iron homeostasis, and ABA signalling (Çevik et al., 2012; Chen et al., 2012; Yang et al., 2014; Liu et al., 2016). In addition, the med25 mutant plants were salt sensitive but drought resistant (Elfving et al., 2011). The strong links described between the Mediator subunits and a wide range of plant stress responses support a putative role for Mediator as the final integration point for multiple, convergent signalling pathways controlling transcriptional output by RNAP II (Yang et al., 2016). Thus, Mediator is in a perfect setting to act as a regulatory hub integrating stress signals from both organelles and other cellular compartments, regulating cellular energy metabolism in response to stress and changes in growth conditions. Possibly the signals are perceived by the conserved KIN10–CDKE1 complex and transduced to the Mediator to initiate the transcriptional response (Fig. 3). However, the mechanism underlying a role for the Mediator as a regulatory hub and the specific involvement of CDKE1 are still unclear. Concluding remarks The organelles produce multiple signals in response to fluctuations in the environment that orchestrate major changes in nuclear gene expression. However, for the plant to respond optimally to environmental stress, information must be integrated from signals originating in different cellular compartments. A common feature following exposure to various stress conditions is an accumulation of ROS and, when environmental factors such as temperature or water availability constrain photosynthetic or respiratory electron transport, ROS accumulates in the organelles. ROS are themselves believed to act as RS molecules, but ROS also inhibits the activity of key enzymes in various biosynthetic pathways, resulting in the accumulation of specific metabolites such as PAP and MEcPP, which also act as signalling molecules in stress-triggered RS (Fig. 2). If and how the different retrograde signals triggered by the same type of stress, such as PAP and ROS, are integrated remains to be determined. In addition, it is necessary for the plant to perceive the signature of the ROS signal to trigger the correct change in gene expression. Identifying the mechanism by which the plant cell can recognize the cellular origin of a specific ROS signal and trigger the appropriate response will be a challenge for the future. It is clear that retrograde signals play an important role during plant stress responses, regulating a large number of genes in response to stress. Operational retrograde signals communicate impaired function of the power-houses of the plant cell, and a switch from growth to stress response is essential for the stress acclimation process. The Mediator complex appears to functions as a regulatory hub to integrate different stress- and energy-related signals, possibly through the kinase module, to control changes in gene expression required for the acclimation to stress (Fig. 3). Further research must address the role of this complex, address whether the individual subunits play specific roles in the stress responses, and determine the nature of signals perceived by Mediator. Abbreviations: Abbreviations: ABA abscisic acid ABI ABA-insensitive alx8 altered expression of APX2 AOX alternative oxidase BBX19 B-box protein 19 BiP binding immunoglobulin protein bZIP basic leucine zipper CAMTA3 CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR3 β-CC β-cyclocitral CDKE1/CDK8 cyclin-dependent kinase E1 ceh1 constitutively expressing hydroperoxyde lyase1 CKM cyclin kinase module of Mediator complex COR cold-regulated DIN6 dark-inducible 6 ER endoplasmic reticulum ETC electron transport chain EX1/EX2 EXECUTER 1/EXECUTER2 flu fluorescent in blue light GUN genomes uncoupled HDS 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase HEN3 HUA ENHANCER 3 H2O2 hydrogen peroxide HPL hydroperoxide lyase HSP heat shock protein HY5 LONG HYPOCOTYL 5 IRE1 INISITOL REQUIRING 1 JA jasmonic acid KIN10 Snf1 kinase homologue 10 MAPK mitogen-activated protein kinase MCS membrane contact site MEcPP 2-C-methyl-d-erythritol 2,4-cyclodiphosphate MED Mediator MgProtoIX Mg2+ protoporphyrin IX 1O2 singlet oxygen O2–· superoxide anion radical PAP 3ʹ-phosphoadenosine 5ʹ-phosphate PCD programmed cell death PhANG photosynthesis-associated nuclear gene PRR5 PSEUDO RESPONSE REGULATOR 5 rao1 regulator of alternative oxidase 1 RNAP II RNA polymerase II ROS reactive oxygen species RS retrograde signalling SA salicylic acid SFR6 SENSITIVE TO FREEZING 6 SnRK1 Snf1-related kinase 1 SORG 1O2-responsive gene TBP tetrapyrrole biosynthesis pathway TF transcription factor UPR unfolded protein response XRN 5ʹ–3ʹ exoribonucleases ZAT zinc finger transcription factor of Arabidopsis thaliana ZTL ZEITLUPE References Aarti PD, Tanaka R, Tanaka A. 2006. 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