A brief overview of the Swi1 prion—[SWI+]

A brief overview of the Swi1 prion—[SWI+] Abstract Prion and prion-like phenomena are involved in the pathology of numerous human neurodegenerative diseases. The budding yeast, Saccharomyces cerevisiae, has a number of endogenous yeast prions—epigenetic elements that are transmitted as altered protein conformations and often manifested as heritable phenotypic traits. One such yeast prion, [SWI+], was discovered and characterized by our laboratory. The protein determinant of [SWI+], Swi1 was found to contain an amino-terminal, asparagine-rich prion domain. Normally, Swi1 functions as part of the SWI/SNF chromatin remodeling complex, thus, acting as a global transcriptional regulator. Consequently, prionization of Swi1 leads to a variety of phenotypes including poor growth on non-glucose carbon sources and abolishment of multicellular features—with implications on characterization of [SWI+] as being detrimental or beneficial to yeast. The study of [SWI+] has revealed important knowledge regarding the chaperone systems supporting prion propagation as well as prion–prion interactions with [PSI+] and [RNQ+]. Additionally, an intricate regulatory network involving [SWI+] and other prion elements governing multicellular features in yeast has begun to be revealed. In this review, we discuss the current understanding of [SWI+] in addition to some possibilities for future study. prion, SWI/SNF, [SWI+], prion-interactions, chaperones, multicellularity INTRODUCTION Protein misfolding, aggregation and amyloid formation underlie a large number of human diseases (Chiti and Dobson 2017). These diseases include several devastating central nervous system degenerative disorders—transmissible spongiform encephalopathies, or prion diseases, which are chief among these protein-folding disorders, as well as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (Prusiner 2013; Walker and Jucker 2015). The proteins in these neurodegenerative diseases—including prion protein (PrP), amyloid beta, tau and alpha-synuclein—all demonstrate the capability to relinquish their native fold and form into amyloid, a cross-beta-sheet-rich structure (Selkoe 1991; Prusiner 1998; Lashuel et al.2013; Spillantini and Goedert 2013). This conformational switch has direct cellular consequences and the associated mechanisms remain important for study of the pathogenesis of the related diseases. Though initially associated with disease states, the prion concept—that is, the ability for a protein to adopt an alternative, self-propagating conformation—has expanded to encompass a variety of functional conformational-switching events in various organisms. Examples of functional prion-like proteins can be found across kingdoms of life including Arabidopsis, fungi, Aplysia, Drosophila, mice and humans (Si et al.2010; Majumdar et al.2012; Cai et al.2014; Stephan et al.2015; Chakrabortee et al.2016b). The identification of novel prion-like proteins and their—as well as already identified prion-like proteins’—role in disease and normal cellular functions continues to be an important focus of research. Meanwhile, the budding yeast, Saccharomyces cerevisiae, has demonstrated to have a multitude of endogenous prions with distinct protein determinants—including [PSI+], [URE3], [RNQ+] (also known as [PIN+]), [SWI+], [OCT+], [GAR+], [MOD+], [NUP100+] and [MOT3+] and their protein determinants of Sup35, Ure2, Rnq1, Swi1, Cyc8, Pma1/Std1, Mod5, Nup100 and Mot3, respectively (Cox 1965; Lacroute 1971; Wickner 1994; Stansfield et al.1995; Derkatch et al. 1997, 2001; Sondheimer and Lindquist 2000; Du et al.2008; Patel, Gavin-Smyth and Liebman 2009; Suzuki, Shimazu and Tanaka 2012; Halfmann et al.2012b; Holmes et al.2013). The focus of this review article, [SWI+], was initially characterized by our laboratory. [SWI+] has acted as a route towards greater understanding of the prion phenomenon and seems to straddle the divide of whether yeast prions ought to be classified as disease states or functional epigenetic elements serving to provide agile adaptive abilities. Uncovering the Swi1 prion Prior to discovering the prion form of Swi1, three yeast amyloid prions, [PSI+], [RNQ+] and [URE3], had already been identified (Cox 1965; Lacroute 1971; Wickner 1994; Stansfield et al.1995; Sondheimer and Lindquist 2000; Derkatch et al.2001). A commonality among the protein determinants of these prions is the existence of regions with a high number of glutamine and asparagine residues. These glutamine/asparagine-rich regions are essential for prion formation and transmission and thus known as prion determination domains (PrDs); however, not all prion proteins have glutamine/asparagine-rich regions (e.g. [MOD+] of yeast, [Het-s] of Podospora anserina and mammalian PrP) (Coustou et al.1997; Suzuki, Shimazu and Tanaka 2012). A bioinformatics search for glutamine/asparagine-rich prion-like domains identified a large number of candidates for prion protein determinants, including multiple components of a yeast chromatin-remodeling complex, the SWI/SNF complex (Michelitsch and Weissman 2000). The identification of Swi1 overexpression as a factor capable of inducing [PSI+]—through what is now known to be due to prion-prion interactions—highlighted the likelihood of Swi1 to act as a prion (Derkatch et al.2001). Using these studies as a route to discovery, our lab focused on investigating whether Swi1 or Snf5 could act as a yeast prion. Both proteins contain regions enriched in asparagine and/or glutamine and are important components of the SWI/SNF complex. As our extensive efforts, including the previous effort of one of us (Li) as part of the Lindquist lab, failed to show that Snf5 can act as a prion, we pivoted to focus our work primarily on Swi1. We hypothesized that in Swi1 overproduction-induced [PSI+] cells, Swi1 has a higher potential to be a prion due to possible promotion of Swi1 to change conformations via prion protein interactions. By co-overexpressing SWI1 and SUP35 constructs, we generated [PSI+] cells that were further screened for [SWI+] by scoring their ability in using raffinose. This examination was based on prions usually showing loss-of-function phenotypes and SWI/SNF mutants (such as swi1Δ) demonstrating an incapacity in using non-glucose carbon sources (Neigeborn and Carlson 1984). Eventually, [PSI+] containing [SWI+] candidates were successfully acquired and exhibited reduced growth on raffinose, glycerol and galactose, which could be reversed by treatment with millimolar concentrations of guanidine hydrochloride (GdnHCl), an Hsp104 chaperone inhibitor that had been previously shown to cure other yeast prions (Tuite, Mundy and Cox 1981; Ferreira et al.2001; Jung and Masison 2001). However, at this point, [SWI+] had only been demonstrated to exist in cells that were also [PSI+]. Further experimentation with Hsp104 overproduction displayed that [SWI+] and [PSI+] are distinct in Hsp104 sensitivity. Since Hsp104 overproduction did not reverse the poor growth on raffinose and such overproduction does cure [PSI+] as reported previously (Chernoff et al.1995), this method was utilized to produce [psi−][SWI+] cells—supporting that [SWI+] could be a separate entity from [PSI+]. To show that [SWI+] was a bonafide prion, other prion characteristics were to be verified. The dominant nature of these epigenetic elements and their cytoplasmic-based inheritance were confirmed via mating and sporulation of diploid cells and classical cytoduction experiments, respectively (Du et al.2008). Swi1 was found to form aggregates in [SWI+] cells, while Snf5 was diffuse and both proteins remained diffuse in [swi−] cells (Du et al.2008). Confirmation of Swi1 as the protein determinant of [SWI+] was shown by the fact that [SWI+] could be cytoduced into snf5Δ cells but failed to be cytoduced into swi1Δ cells, indicating that Swi1 expression as necessary for [SWI+]. The fact that overexpression of just the non-asparagine/glutamine-rich carboxyl-terminal region of Swi1 could rescue the raffinose phenotype of [SWI+] provided further evidence (Du et al.2008). Additionally, Alberti and others were able to use the same [PSI+]-based co-induction and a Sup35-assay—among other methods—to confirm that Swi1 was a prion protein that can exist in the form of [SWI+] (Alberti et al.2009). Based on the modularity of PrDs, the Sup35-assay uses the fusion of a PrD of interest with the MC (or just C) regions of Sup35 to replace the endogenous Sup35, with observation of cells for the [PSI+]-like phenotype upon expression (Sondheimer and Lindquist 2000; Alberti et al.2009). Thus, we had proved Swi1 can be a prion, the first of several identified prion proteins involved in global transcriptional regulation of gene expression. Defining the prion domain of Swi1 Dividing the Swi1 protein based on amino-acid composition offered three distinct regions (Fig. 1A). The amino-terminal N region was rich in asparagine residues, the middle Q region was rich in glutamine residues and the carboxyl-terminal C region previously mentioned was enriched in neither. Given that overexpression of the C region of Swi1 was able to restore Swi1 function in either deletion or prion contexts, we demonstrated that the C region contains the functional domain and that the N and Q regions were basically dispensable for SWI/SNF function (Du et al.2010). Figure 1. View largeDownload slide A schematic diagram showing Swi1 protein organization. (A) The Swi1 protein consists of three regions. The N region is highly enriched in asparagine (N) residues, holds the prion domain (PrD) and can form fibrils to seed [SWI+] formation (Du et al.2010). The middle Q region is rich in glutamine (Q) residues and modulates the aggregation pattern of the N region and Swi1 functions. The C-terminal located C region harbors the functional domain of Swi1. (B) The sequence of the N region is shown. The extreme N-terminal region, Swi11–38—shown to be able to stably transmit the prion confirmation in the absence of full-length Swi1—is underlined in black (Crow, Du and Li 2011). A reported amyloidogenic region, Swi1239–259, whose role in prionogenesis has not been tested, is also underlined (in green) (Sant’Anna et al.2016). Asparagine and glutamine residues are highlighted in red and blue, respectively. Figure 1. View largeDownload slide A schematic diagram showing Swi1 protein organization. (A) The Swi1 protein consists of three regions. The N region is highly enriched in asparagine (N) residues, holds the prion domain (PrD) and can form fibrils to seed [SWI+] formation (Du et al.2010). The middle Q region is rich in glutamine (Q) residues and modulates the aggregation pattern of the N region and Swi1 functions. The C-terminal located C region harbors the functional domain of Swi1. (B) The sequence of the N region is shown. The extreme N-terminal region, Swi11–38—shown to be able to stably transmit the prion confirmation in the absence of full-length Swi1—is underlined in black (Crow, Du and Li 2011). A reported amyloidogenic region, Swi1239–259, whose role in prionogenesis has not been tested, is also underlined (in green) (Sant’Anna et al.2016). Asparagine and glutamine residues are highlighted in red and blue, respectively. Expression of varying constructs of combinations of the Swi1 protein regions (N, NQ, QC, C) would elucidate which regions were sufficient and necessary for [SWI+]. Fluorescently tagged versions of N and NQ were the only constructs to exhibit aggregation in [SWI+] cells, thus the Q and C regions were not necessary for the aggregation phenotype (Du et al.2010). One aspect that was noted to be affected by the inclusion of the Q region was the typical pattern of aggregation. We speculated that this change in aggregation pattern may be due to protein interactions mediated by the Q region—such as those via the possible actin-binding domain present in this region (Du et al.2010). Also, expression of QC instead of just the C region alone demonstrated a better ability to rescue the lack of growth of swi1Δ cells on raffinose media—suggesting a role for the Q region in normal Swi1 function (Du et al.2010). Further support for the N region containing the Swi1 PrD would come from the fact that chromosomal deletion of the N region of Swi1 resulted in cells unable to maintain [SWI+] and unable to have [SWI+] cytoduced (Du et al.2010). Additionally, the recombinant N region of Swi1 formed amyloid fibrils in vitro with infectivity observed via fibril transformation experiments (Du et al.2010). Therefore, the N region includes the Swi1 PrD. To further characterize this amino-terminal PrD, truncation experiments revealed that the extreme amino-terminal of Swi1 acts as a major determinant for [SWI+]. The truncation of the N region (Swi11–323) down to Swi11–38 still conserved the ability to aggregate in [SWI+] cells and maintain and propagate [SWI+] in the absence of full-length Swi1 (Crow, Du and Li 2011). Importantly, this small region could also transmit [SWI+] back to full-length Swi1. Meanwhile, constructs not containing this extreme amino-terminal region (e.g. Swi155–327) were unable to support [SWI+] propagation. Interestingly, Swi11–38 consisted of an extremely asparagine-rich region that was also glutamine-free (Fig. 1B). Upon further inspection, smaller amino-terminal regions (down to, and including Swi11–32) were found to be able to co-aggregate with full-length Swi1 in [SWI+] cells, maintain the prion fold in the absence of the full-length protein and transmit the prion conformation back to full-length Swi1 (Valtierra, Du and Li 2017). In addition, when full-length Swi1 was overexpressed, other smaller truncations (down to, and including Swi11–28) aggregated in [SWI+] cells—although these smaller constructs could not stably maintain [SWI+] as the prion would be quickly lost upon passaging. Intriguingly, a few such small Swi1 amino-terminal truncations were capable of acting as valid PrDs to support de novo prion formation and transmission of a chimeric prion. This capability was demonstrated via the classic Sup35 assay (Sondheimer and Lindquist 2000). In this assay, Swi11–38, Swi11–32 and Sw11–31 all could recapitulate the [PSI+]-like phenotype as artificial prions ([SPS+]) when fused with the MC region of Sup35 (Valtierra, Du and Li 2017). Further work is necessary to determine the roles of the extreme amino-terminal region (∼30 amino acids) in Swi1 prion de novo formation and propagation regarding the prion-forming frequency, stabilization and interactions with other proteins. Meanwhile, another recent study utilized bioinformatics to predict and confirm that there is an additional amyloid-forming region (Swi1239–259) within the Swi1 PrD but beyond the amino-terminal region we have examined (Sant’Anna et al.2016). It remains to be determined if this region is prionogenic or contributes to [SWI+] formation and propagation events. Chaperone effects on [SWI+] A suite of chaperones in yeast provides the ability for prions to be maintained and propagate. The chaperone system composed of Hsp104, Hsp70 and Hsp40 has been shown to be essential for propagating all amyloid prions (Liebman and Chernoff 2012). To allow for one part of this chaperone system, the disaggregase, Hsp104 to bind, other chaperones (Hsp70 and Hsp40) must initially bind to the target protein (Chernova, Wilkinson and Chernoff 2017). Once bound, Hsp104 acts on prion aggregates to fragment them and, thus, generates propagons or prion seeds for passing the prion to daughter cells (Cox, Ness and Tuite 2003; Kryndushkin et al.2003). Most yeast prions are highly susceptible to Hsp104 disruption but only [PSI+] is susceptible to Hsp104 overproduction (Crow and Li 2011; Liebman and Chernoff 2012). [SWI+] cells can be readily cured through either Hsp104 inactivation through GdnHCl treatment or ectopic expression of a dominant-negative Hsp104 mutant (Du et al.2008; Valtierra, Du and Li 2017). However, like [RNQ+] and [URE3] but not [PSI+], [SWI+] was not found to be susceptible to elimination via overexpression of HSP104. Another crucial class of chaperones for yeast prions is the Hsp70s, which consists of a family of six different proteins (Ssa1, Ssa2, Ssa3, Ssa4, Ssb1, Ssb2) (Craig et al.1995). Hsp70 chaperones were shown as important modulators of [PSI+] propagation (Jung et al.2000; Jones et al.2004; Allen et al.2005). In addition to these proteins, a number of co-chaperones exist that together with the Hsp70s act as concerted machinery (Sharma and Masison 2009). These additional proteins include J-proteins and nucleotide exchange factors (NEFs). Disruptions to any of these proteins may disrupt a yeast prion's ability to be stably maintained and propagate (Sondheimer et al.2001; Kryndushkin et al.2002; Aron et al.2007; Fan et al.2007; Kryndushkin and Wickner 2007; Higurashi et al.2008; Sadlish et al.2008; Sharma and Masison 2009; Hines et al.2011). [SWI+], in particular, has been shown to be very sensitive to such disruptions. When a mutant of Ssa1, Ssa1-21 was expressed, this dominant negative variant managed to cure [SWI+] in all observed colonies (Hines et al.2011). On the other hand, the same experiment conducted with [PSI+] cells instead displayed only infrequent loss of [PSI+] (Jung et al.2000). This sensitivity of [SWI+] to perturbation of the Hsp70 system extends to its co-chaperones. Among the NEFs in yeast are Sse1 and Sse2, which are classified as Hsp110s and can function as the NEFs of Hsp70 (Dragovic et al.2006; Raviol et al.2006). In accordance to previous data showing that the presence of Sse1 was important for propagation of some other yeast prions, [SWI+] was examined for a similar dependence. Deletion of Sse1 leads to complete elimination of [SWI+], indicating reliance on Sse1 (Fan et al.2007; Kryndushkin and Wickner 2007; Hines et al.2011). Additionally, the study found that overexpression of either Sse1 or Sse2 could also destabilize [SWI+] in a 74D-694 strain. However, recent results from a separate investigation has revealed that similar Sse1 overexpression in a BY4741 strain cannot cure [SWI+]—indicating strain-specific effects (Du et al.2017). Moreover, Sse1 was shown to still function in maintaining and propagating [SWI+] as overexpression of Sse1 in the same BY4741 strain hindered curing via GdnHCl (Du et al.2017). These results indicate the sensitive role of Sse1/2 in [SWI+] maintenance and propagation and that such sensitivity may vary from strain-to-strain. [SWI+] was found to be sensitive to the overexpression of multiple different Hsp40s (J-proteins). When the J-proteins Sis1, Ydj1 or Apj1 were constitutively overexpressed from a plasmid, [SWI+] was lost in the majority of colonies via observation of Swi1 aggregation. In fact, even overexpression of just the J-domain of these J-proteins produced a similar effect. Additionally, repression of Sis1 expression was found to eliminate [SWI+] over multiple generations—likely due to an effect on [SWI+] propagation and thus indicating the need for Sis1 in propagating [SWI+] just like other prions (Sondheimer et al.2001; Aron et al.2007; Higurashi et al.2008). Meanwhile, another noteworthy interplay between [SWI+] and the J-proteins was the finding that deletion of the entirety of Ydj1 or just the carboxyl-terminal domain of Ydj1 also eliminated [SWI+]—again suggesting that this region of this protein was critical to [SWI+] propagation. Overexpression of a similar J-protein, Apj1 was able to partially rescue this loss of [SWI+]—demonstrating possible redundancy of the chaperone system (Hines et al.2011). The disruption of these select J-proteins display significant disruption of [SWI+] propagation; however, given that there are overlaps between J-protein functions in providing support for prion propagation, there may exist yeast strain-specific or [SWI+] variant-specific effects of disruption of individual J-proteins. This large combination of necessities and possible routes of destabilization indicates that [SWI+] is uniquely sensitive to perturbations of and uniquely reliant on the Hsp40/Hsp70 system. Hines and others hypothesized that this sensitivity may allow for more rapid adaptation to the environment due to being able to more quickly lose [SWI+] (Hines et al.2011). Phenotypes affected by [SWI+] Studying [SWI+] has been made possible via the multiple phenotypes that the prion confers to yeast (Fig. 2). First amongst these phenotypes was the poor growth on non-glucose carbon sources including raffinose, galactose, glycerol and sucrose. For example, [SWI+] cells grow at a significantly slower rate on raffinose media—providing a partial loss of function phenotype (Du et al.2008). Figure 2. View largeDownload slide Yeast cells harboring [SWI+] display a variety of phenotypes. Shown are major characterized phenotypes of the [SWI+] prion in yeast. Moving from left to right: by expression from a plasmid, fluorescently tagged Swi1 or a Swi1-PrD-containing fragment (e.g. NQ-YFP) aggregates in [SWI+] but is diffuse in [swi−] cells (Du et al. 2008, 2010). [SWI+]-containing cells exhibit poor growth on non-glucose carbon sources such as raffinose compared to [swi−] cells as shown (Du et al.2008). Multicellular features including flocculation, adhesive growth (observed via crystal blue staining after washing) and diploid pseudohyphae formation on SLAD (synthetic low ammonium dextrose) media are abolished in the presence of [SWI+] (Du, Zhang and Li 2015). [SWI+] cells are easily washed away in a wash assay and display enhanced mobility and an ability to migrate in flowing water in the illustrated raindrop assay (Newby and Lindquist 2017). Figure 2. View largeDownload slide Yeast cells harboring [SWI+] display a variety of phenotypes. Shown are major characterized phenotypes of the [SWI+] prion in yeast. Moving from left to right: by expression from a plasmid, fluorescently tagged Swi1 or a Swi1-PrD-containing fragment (e.g. NQ-YFP) aggregates in [SWI+] but is diffuse in [swi−] cells (Du et al. 2008, 2010). [SWI+]-containing cells exhibit poor growth on non-glucose carbon sources such as raffinose compared to [swi−] cells as shown (Du et al.2008). Multicellular features including flocculation, adhesive growth (observed via crystal blue staining after washing) and diploid pseudohyphae formation on SLAD (synthetic low ammonium dextrose) media are abolished in the presence of [SWI+] (Du, Zhang and Li 2015). [SWI+] cells are easily washed away in a wash assay and display enhanced mobility and an ability to migrate in flowing water in the illustrated raindrop assay (Newby and Lindquist 2017). In contrast, another phenotype of [SWI+], the loss of multicellular features such as flocculation, invasive growth and pseudohyphae formation provides a complete loss of function phenotype (Du, Zhang and Li 2015). [SWI+] cells can be easily observed to have abolished ability to flocculate in liquid media. A simple wash assay displays the lack of invasive growth of prion cells versus non-prion and diploids can be examined for the loss of any pseudohyphae formation. Note that in order for [swi−] cells to demonstrate the multicellular phenotypes, it may require repair of the FLO8 gene in some lab strains (e.g. 74-D694 and S288C). By taking advantage of the tight regulation of the FLO genes by Swi1, a reporter system was established by replacing the FLO1 gene with URA3 at its chromosomal locus, which allows for selection for and against [SWI+] using 5-fluroorotic acid and uracil-deficient selective media, respectively (Du et al.2017). The aggregation phenotype of [SWI+] can be observed via transformation of marker plasmids expressing Swi1 that is fluorescently tagged—e.g. Swi1-YFP or Swi1NQ-YFP. The exact aggregation pattern observed with these plasmids may vary depending on the construct utilized. For example, in [SWI+] cells and in the presence of endogenous full-length Swi1, Swi1N-YFP tends to have a large portion of the cells containing single large aggregates, Swi1NQ-YFP more frequently displays multiple small aggregates, and full-length Swi1-YFP features a mix of both types of aggregates (Du et al.2010). Numerous studies show that yeast prions can display evolutionarily advantageous traits and thus are beneficial (True and Lindquist 2000; True, Bedin and Lindquist 2004; Halfmann et al.2012a; Holmes et al.2013; Jarosz et al.2014; Chakrabortee et al.2016a). However, it has also been argued that some prions, such as [PSI+] and [URE3], are diseases of yeast due to a variety of factors including the presence of detrimental phenotypes and induction of proteins tied to the stress response (Wickner et al.2011). The phenotypes of poor growth on non-glucose carbon sources and abolishment of multicellular features both may suggest that [SWI+] is associated with a disease state. The observed instability of [SWI+] may point to the prion being an unwanted feature. However, as the conversion frequency of [SWI+] is also higher than [PSI+], the ability of [SWI+] to be easily lost or gained may possibly provide yeast with a flexibility and capacity to rapidly adapt to the environment through selection (Lancaster et al.2010; Hines et al.2011; Du et al.2017). Indeed, research demonstrates that [SWI+] may also offer beneficial, functional phenotypic adaptations. When compared to isogenic [swi−] cells, [SWI+] cells were shown to have greater resistance to the microtubule-inhibiting fungicide benomyl in certain strains—demonstrating that the [SWI+] prion can be beneficial under certain conditions (Alberti et al.2009). Although it is largely believed that multicellular features help yeast to survive poor nutrient conditions and protect cells from various stresses (Granek and Magwene 2010; Brückner and Mösch 2012), we previously speculated that under optimal growth conditions, yeast may favor the unicellular form (Du, Zhang and Li 2015). The unicellular form would provide the yeast cells the ability to freely migrate and quickly multiply and thus, conversion between [SWI+] and [swi−] would allow cells to sense and adapt to environmental changes through gain or loss of multicellular features. Indeed, recent research has shown that the loss, via [SWI+], of multicellular features allows for enhanced mobility of yeast (Fig. 2; Newby and Lindquist 2017). These cells, termed pioneers, offer possible advantages in some environmental situations. The lack of multicellular features allows for easier water-based migration of the cells as originally observed in a wash assay (Du, Zhang and Li 2015). Another water-based assay, the raindrop assay further demonstrated this fact and portrays prion cells as allowing yeast to travel with water flow and grow in new regions—providing access to additional nutrients and a corresponding boost to fitness (Newby and Lindquist 2017). This relatively new assay and pseudo-environmental phenotype provides a glimpse into the possibility of [SWI+] and other yeast prions acting as quick adaptive mechanisms. Lastly, the previously known requirement for Swi1 function for expression of the HO gene, which allows for mating type switching, creates another malleable phenotype (Stern, Jensen and Herskowitz 1984). Prionization of Swi1 in the form of [SWI+] leads to a likely decrease in HO expression and mating-type switching. As such, Newby and Lindquist reported that [SWI+] spores demonstrate an increased rate of out-crossing—mating of mother cells with non-daughter cells—compared to [swi−] spores (Newby and Lindquist 2017). This enhancement of out-crossing and the reduction of inbreeding were due to the disability of [SWI+] cells in mating-type switching and was eliminated with loss of the prion. The increased out-crossing may increase genetic variation and thus provide an advantage to prion cells in diverse environments. Additional phenotypes of [SWI+] likely remain to be uncovered since the role of Swi1 as a global transcription regulator allows for possible impact on a wide range of yeast phenotypes. To reveal such novel phenotypes, a genomics-focused approach may be appropriate. For example, RNA sequencing (RNA-seq) could reveal differences between [SWI+], [swi−] and swi1Δ cells—providing a clearer picture of the transcriptional impact of the prion. Moreover, pairing such methodology with a systematic phenotypic assay would provide a strong probability of identifying additional [SWI+] phenotypes that could be deleterious or beneficial in nature. Regulation of multicellular features by yeast prions Following the discovery of [SWI+], additional studies identified several new yeast prions including [OCT+], [GAR+], [MOD+], [NUP100+] and [MOT3+] (Brown and Lindquist 2009; Patel, Gavin-Smyth and Liebman 2009; Suzuki, Shimazu and Tanaka 2012; Halfmann et al.2012b; Holmes et al.2013). The protein determinants for these prions—Cyc8, Pma1/Std1, Mod5, Nup100 and Mot3, respectively—feature additional transcriptional regulators (Cyc8 and Mot3); the fact that several transcriptional regulators could act as prions has been extensively discussed (Alberti et al.2009; Du 2011; Du, Zhang and Li 2015). Of particular importance was the possibility of prion–prion interactions in concert with transcriptional interactions to regulate key yeast processes. Along with Swi1, the yeast prion proteins of Cyc8, Mot3 and Ure2 (via regulation of Gln3) have noted regulatory targets involving multicellular features of yeast including flocculation, pseudohyphae development and invasive growth (Barrales, Jimenez and Ibeas 2008; Barrales et al.2012; Holmes et al.2013). As the yeast SWI/SNF complex regulates the transcription of approximately 6% of the genome by one estimation (Sudarsanam et al.2000), prionization of Swi1 was hypothesized to greatly affect the transcriptional profile of cells and thus the phenotypes observed. The regulation of the flocculin (FLO) genes by SWI/SNF, and thus, Swi1, provided a mechanism for [SWI+] to abolish the aforementioned multicellular features. Indeed, this has been shown to occur in the presence of [SWI+] (Fig. 3; Du, Zhang and Li 2015). Interestingly, other FLO gene transcriptional activators—such as Mss11 and Sap30—co-aggregate with Swi1 and are titrated by [SWI+] (Du, Zhang and Li 2015), causing abolishment instead of reduction of multicellular features. This setup alone makes for an elegant regulation of phenotypes that can be critical to yeast survival. Figure 3. View largeDownload slide Regulation of multicellular features by prion proteins in yeast. The yeast prion proteins of Swi1, Cyc8 and Mot3 are regulators of FLO gene expression. In the non-prion state, Swi1 (as a component of the SWI/SNF chromatin remodeling complex) promotes FLO gene expression; Mot3 and Cyc8 (subunit of the Cyc8-Tup1 co-repressor complex) act as transcriptional repressors of FLO genes (Barrales et al.2012; Holmes et al.2013). The [MOT3+] prion promotes multicellular features by enhancing FLO gene expression, whereas [SWI+] abolishes FLO gene expression and thus eliminates multicellular features (Holmes et al.2013; Du, Zhang and Li 2015). The Cyc8 prion ([OCT+]) would be predicted to remove a source of repression and, thus, increase FLO gene expression. Yeast can harbor multiple prions and the interaction among the three prions may intricately modulate FLO gene expression. Figure 3. View largeDownload slide Regulation of multicellular features by prion proteins in yeast. The yeast prion proteins of Swi1, Cyc8 and Mot3 are regulators of FLO gene expression. In the non-prion state, Swi1 (as a component of the SWI/SNF chromatin remodeling complex) promotes FLO gene expression; Mot3 and Cyc8 (subunit of the Cyc8-Tup1 co-repressor complex) act as transcriptional repressors of FLO genes (Barrales et al.2012; Holmes et al.2013). The [MOT3+] prion promotes multicellular features by enhancing FLO gene expression, whereas [SWI+] abolishes FLO gene expression and thus eliminates multicellular features (Holmes et al.2013; Du, Zhang and Li 2015). The Cyc8 prion ([OCT+]) would be predicted to remove a source of repression and, thus, increase FLO gene expression. Yeast can harbor multiple prions and the interaction among the three prions may intricately modulate FLO gene expression. Compounding this [SWI+]-driven regulation of FLO gene expression and multicellular features was the additional regulation of the same features or genes by Mot3. A prior investigation of Mot3 demonstrated the ability of yeast to gain multicellular features such as biofilm formation and invasive growth via prionization of Mot3 ([MOT3+]) (Holmes et al.2013). This event may then act as a boost to the fitness of the [MOT3+] yeast—demonstrating the prion to act in a functional fashion rather than perpetuating a disease-state. Interestingly, this regulation of yeast multicellularity by [MOT3+] exists in noted opposition to [SWI+]. Mot3 normally represses FLO gene expression, while Swi1 promotes FLO gene expression. Prionization de-represses expression in the case of [MOT3+], while [SWI+] un-induces expression (Fig. 3). A layered regulation of yeast multicellularity was thus identified via the studies of these two prions. To further complicate the regulation of these important but limited phenotypes, the protein determinant of [OCT+], Cyc8 enters the ring (Patel, Gavin-Smyth and Liebman 2009). The normal function of Cyc8 is transcriptional control—including acting as an inhibitor of FLO gene expression in conjunction with Tup1 (Fig. 3; Barrales, Jimenez and Ibeas 2008). Thus, one additional layer of regulation may exist where the non-prion form of Cyc8 inhibits FLO gene expression and its prionization disinhibits expression (Fig. 3). It should be noted that there are multiple FLO genes and each gene may be differentially targeted by the yeast prion proteins such as Swi1, Mot3 and Cyc8 and that each gene may have variable roles in the multitude of multicellular phenotypes—increasing the complexity of regulation. Additionally, other yeast proteins capable of forming prions may also play a role in the regulation of these particular genes—or other overlapping targets for unrelated phenotypes. Furthermore, the possibility for yeast to harbor multiple of the FLO gene-regulating prions at once provides an opportunity for intricate regulation. Combined with probable prion–prion interactions between [SWI+], [MOT3+] and [OCT+] and possibly [URE3], a significant and multi-layered transcriptional network likely exists that remains to be fully uncovered. Characterizing prion–prion interactions of [SWI+] It is well-documented that a single yeast cell can harbor more than one prion element and that when two prions co-exist, they influence not only each other's de novo appearance but also propagation (Derkatch et al. 1997, 2001, 2004). Investigation of prion–prion interactions—such as those examined in the yeast system—has particular significance as it may aid in uncovering pathological mechanisms in neurological disorders where interactions between amyloidogenic and/or prion-like proteins are highlighted (Clinton et al.2010; Ono et al.2012; Guo et al.2013). Saccharomyces cerevisiae has provided ample opportunity to investigate interactions between different endogenous prions, various prion strains, as well as exogenously expressed prion-like proteins (Meriin et al.2002). As noted earlier, overexpression of Swi1 had been shown to induce the appearance of [PSI+] (Derkatch et al.2001; Du et al.2008). These data highlighted the likelihood that [SWI+] would similarly be shown to be capable of inducing [PSI+]. Indeed, further study revealed that [SWI+] increases the formation rate of both [PSI+] and [RNQ+] and that a cross-seeding mechanism was likely responsible (Du and Li 2014). The ability for a yeast cell to contain at least three distinct prions—[PSI+], [RNQ+] and [SWI+]—was also documented. However, colocalization of these prion proteins was found to vary based on the maturity of the aggregates with colocalization (and thus interactions) being restricted primarily to the early, or initiation, stage of prion formation (Du and Li 2014). In addition, [PSI+] and [RNQ+] have been demonstrated to affect the formation rate of [SWI+]. Utilizing the FLOpr-URA3 reporter system, the spontaneous de novo formation rate of [SWI+] in non-prion cells was found to be approximately 5 × 10−4 in the S288C lab strain and 4 × 10−5 in the 74D-694 lab strain (Du et al.2017). However, the presence of [PSI+] or [RNQ+] was shown to increase this de novo formation rate by a factor of 100 or 10, respectively (Du et al.2017). These increases as well as the previously discussed reports demonstrate that [PSI+], [RNQ+] and [SWI+] can mutually promote the formation of one another. An additional example of prion–prion interaction with [SWI+] and [RNQ+] was reported in the form of [NSI+], a non-Mendelian genetic factor exhibiting a suppression of nonsense mutations in yeast strains with a deleted or modified Sup35 N-terminal domain (Saifitdinova et al.2010). Initially characterized as an element with many prion qualities, the protein determinant was later reported to consist of an interaction between [SWI+] and [RNQ+] rather than a novel prion protein in a specific yeast strain background (Nizhnikov et al.2016). Whereas [SWI+] on its own recapitulated a mild form of the [NSI+] nonsense suppression via reduction of Sup45 expression, [RNQ+] enhanced this phenotype further thus creating what was previously identified as the [NSI+] phenotype (Nizhnikov et al.2016). Further studies may reveal additional combinatorial phenotypes between [SWI+] and other yeast prions—particularly possible with the aforementioned trifecta of FLO gene regulators. The possibility of combinations of the yeast prions that may help govern yeast multicellularity—[SWI+], [MOT3+] and [OCT+]—could lead to an agile adaptive mechanism. Moreover, interactions between these prions may inherent biases towards certain phenotypes while maintaining what has been previously described as a ‘bet-hedging’ system. The possibility of the development of intermediate or mixed phenotypes on an individual or population level, respectively, also exists. Such phenotypes would better suit the wide range of prospective environmental conditions. CONCLUDING REMARKS Through the discovery, characterization, and further investigation of the Swi1 prion, [SWI+], much insight has been gained on the prion biology. The identification of [SWI+] and Swi1 as its prion determinant in yeast was the first identification of a global transcriptional regulator being able to form a prion (Du et al.2008). A small, asparagine-rich extreme amino-terminal region has been described as the major determinant of [SWI+], and the ability of this region to propagate and maintain [SWI+] is notable (Crow, Du and Li 2011; Valtierra, Du and Li 2017). [SWI+] has also displayed important and varied interplay with other yeast prions including [PSI+] and [RNQ+]—developing the knowledge regarding prion–prion interactions and formation of prions (Du and Li 2014; Nizhnikov et al.2016; Du et al.2017). And perhaps most significant from an evolutionary standpoint, [SWI+] has been demonstrated as a crucial regulator of yeast multicellularity as part of a yet-to-be fully understood network of multiple yeast prions and other proteins (Du, Zhang and Li 2015). Additionally, as a limited number of conditions have been investigated for [SWI+] conferring a selective advantage, there may exist other conditions where the prion demonstrates to be advantageous. Expanding beyond the contributions of [SWI+] research to the understanding of yeast prions and prion networks, the human SWI/SNF complex (also known as the BAF complex) includes components that may be similarly prone to aggregation—perhaps of a prion-like nature—as Swi1. The highly conserved nature of the SWI/SNF chromatin remodeling complex through eukaryotes makes investigation of the human BAF complex tantamount. The likelihood that the BAF complex harbors aggregating proteins proves enticing as a possible target for disease treatment. Human diseases ranging from numerous types of cancers to serious neurodevelopmental disorders have correlations to the erroneous or lost function of the BAF complex (Son and Crabtree 2014; Kadoch and Crabtree 2015). Interestingly, recent research has shown that fusion of the prion-like domain of the EWS protein with the FLI1 transcription factor can act to change the genes targeted by the BAF complex in cancer (Boulay et al.2017). Perhaps direct aggregation—maybe in a prion-like fashion—of BAF complex proteins contributes to the multitude of pathological avenues in these diseases. Acknowledgements The authors would like to dedicate this article to Susan Lindquist, an excellent mentor, outstanding researcher and inspiring leader in the yeast prion field. Her many important contributions to science will be remembered. FUNDING This work is supported by a grant from the U.S. National Institutes of Health (R01GM110045) to LL. Conflicts of interest. None declare. 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A brief overview of the Swi1 prion—[SWI+]

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Abstract

Abstract Prion and prion-like phenomena are involved in the pathology of numerous human neurodegenerative diseases. The budding yeast, Saccharomyces cerevisiae, has a number of endogenous yeast prions—epigenetic elements that are transmitted as altered protein conformations and often manifested as heritable phenotypic traits. One such yeast prion, [SWI+], was discovered and characterized by our laboratory. The protein determinant of [SWI+], Swi1 was found to contain an amino-terminal, asparagine-rich prion domain. Normally, Swi1 functions as part of the SWI/SNF chromatin remodeling complex, thus, acting as a global transcriptional regulator. Consequently, prionization of Swi1 leads to a variety of phenotypes including poor growth on non-glucose carbon sources and abolishment of multicellular features—with implications on characterization of [SWI+] as being detrimental or beneficial to yeast. The study of [SWI+] has revealed important knowledge regarding the chaperone systems supporting prion propagation as well as prion–prion interactions with [PSI+] and [RNQ+]. Additionally, an intricate regulatory network involving [SWI+] and other prion elements governing multicellular features in yeast has begun to be revealed. In this review, we discuss the current understanding of [SWI+] in addition to some possibilities for future study. prion, SWI/SNF, [SWI+], prion-interactions, chaperones, multicellularity INTRODUCTION Protein misfolding, aggregation and amyloid formation underlie a large number of human diseases (Chiti and Dobson 2017). These diseases include several devastating central nervous system degenerative disorders—transmissible spongiform encephalopathies, or prion diseases, which are chief among these protein-folding disorders, as well as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (Prusiner 2013; Walker and Jucker 2015). The proteins in these neurodegenerative diseases—including prion protein (PrP), amyloid beta, tau and alpha-synuclein—all demonstrate the capability to relinquish their native fold and form into amyloid, a cross-beta-sheet-rich structure (Selkoe 1991; Prusiner 1998; Lashuel et al.2013; Spillantini and Goedert 2013). This conformational switch has direct cellular consequences and the associated mechanisms remain important for study of the pathogenesis of the related diseases. Though initially associated with disease states, the prion concept—that is, the ability for a protein to adopt an alternative, self-propagating conformation—has expanded to encompass a variety of functional conformational-switching events in various organisms. Examples of functional prion-like proteins can be found across kingdoms of life including Arabidopsis, fungi, Aplysia, Drosophila, mice and humans (Si et al.2010; Majumdar et al.2012; Cai et al.2014; Stephan et al.2015; Chakrabortee et al.2016b). The identification of novel prion-like proteins and their—as well as already identified prion-like proteins’—role in disease and normal cellular functions continues to be an important focus of research. Meanwhile, the budding yeast, Saccharomyces cerevisiae, has demonstrated to have a multitude of endogenous prions with distinct protein determinants—including [PSI+], [URE3], [RNQ+] (also known as [PIN+]), [SWI+], [OCT+], [GAR+], [MOD+], [NUP100+] and [MOT3+] and their protein determinants of Sup35, Ure2, Rnq1, Swi1, Cyc8, Pma1/Std1, Mod5, Nup100 and Mot3, respectively (Cox 1965; Lacroute 1971; Wickner 1994; Stansfield et al.1995; Derkatch et al. 1997, 2001; Sondheimer and Lindquist 2000; Du et al.2008; Patel, Gavin-Smyth and Liebman 2009; Suzuki, Shimazu and Tanaka 2012; Halfmann et al.2012b; Holmes et al.2013). The focus of this review article, [SWI+], was initially characterized by our laboratory. [SWI+] has acted as a route towards greater understanding of the prion phenomenon and seems to straddle the divide of whether yeast prions ought to be classified as disease states or functional epigenetic elements serving to provide agile adaptive abilities. Uncovering the Swi1 prion Prior to discovering the prion form of Swi1, three yeast amyloid prions, [PSI+], [RNQ+] and [URE3], had already been identified (Cox 1965; Lacroute 1971; Wickner 1994; Stansfield et al.1995; Sondheimer and Lindquist 2000; Derkatch et al.2001). A commonality among the protein determinants of these prions is the existence of regions with a high number of glutamine and asparagine residues. These glutamine/asparagine-rich regions are essential for prion formation and transmission and thus known as prion determination domains (PrDs); however, not all prion proteins have glutamine/asparagine-rich regions (e.g. [MOD+] of yeast, [Het-s] of Podospora anserina and mammalian PrP) (Coustou et al.1997; Suzuki, Shimazu and Tanaka 2012). A bioinformatics search for glutamine/asparagine-rich prion-like domains identified a large number of candidates for prion protein determinants, including multiple components of a yeast chromatin-remodeling complex, the SWI/SNF complex (Michelitsch and Weissman 2000). The identification of Swi1 overexpression as a factor capable of inducing [PSI+]—through what is now known to be due to prion-prion interactions—highlighted the likelihood of Swi1 to act as a prion (Derkatch et al.2001). Using these studies as a route to discovery, our lab focused on investigating whether Swi1 or Snf5 could act as a yeast prion. Both proteins contain regions enriched in asparagine and/or glutamine and are important components of the SWI/SNF complex. As our extensive efforts, including the previous effort of one of us (Li) as part of the Lindquist lab, failed to show that Snf5 can act as a prion, we pivoted to focus our work primarily on Swi1. We hypothesized that in Swi1 overproduction-induced [PSI+] cells, Swi1 has a higher potential to be a prion due to possible promotion of Swi1 to change conformations via prion protein interactions. By co-overexpressing SWI1 and SUP35 constructs, we generated [PSI+] cells that were further screened for [SWI+] by scoring their ability in using raffinose. This examination was based on prions usually showing loss-of-function phenotypes and SWI/SNF mutants (such as swi1Δ) demonstrating an incapacity in using non-glucose carbon sources (Neigeborn and Carlson 1984). Eventually, [PSI+] containing [SWI+] candidates were successfully acquired and exhibited reduced growth on raffinose, glycerol and galactose, which could be reversed by treatment with millimolar concentrations of guanidine hydrochloride (GdnHCl), an Hsp104 chaperone inhibitor that had been previously shown to cure other yeast prions (Tuite, Mundy and Cox 1981; Ferreira et al.2001; Jung and Masison 2001). However, at this point, [SWI+] had only been demonstrated to exist in cells that were also [PSI+]. Further experimentation with Hsp104 overproduction displayed that [SWI+] and [PSI+] are distinct in Hsp104 sensitivity. Since Hsp104 overproduction did not reverse the poor growth on raffinose and such overproduction does cure [PSI+] as reported previously (Chernoff et al.1995), this method was utilized to produce [psi−][SWI+] cells—supporting that [SWI+] could be a separate entity from [PSI+]. To show that [SWI+] was a bonafide prion, other prion characteristics were to be verified. The dominant nature of these epigenetic elements and their cytoplasmic-based inheritance were confirmed via mating and sporulation of diploid cells and classical cytoduction experiments, respectively (Du et al.2008). Swi1 was found to form aggregates in [SWI+] cells, while Snf5 was diffuse and both proteins remained diffuse in [swi−] cells (Du et al.2008). Confirmation of Swi1 as the protein determinant of [SWI+] was shown by the fact that [SWI+] could be cytoduced into snf5Δ cells but failed to be cytoduced into swi1Δ cells, indicating that Swi1 expression as necessary for [SWI+]. The fact that overexpression of just the non-asparagine/glutamine-rich carboxyl-terminal region of Swi1 could rescue the raffinose phenotype of [SWI+] provided further evidence (Du et al.2008). Additionally, Alberti and others were able to use the same [PSI+]-based co-induction and a Sup35-assay—among other methods—to confirm that Swi1 was a prion protein that can exist in the form of [SWI+] (Alberti et al.2009). Based on the modularity of PrDs, the Sup35-assay uses the fusion of a PrD of interest with the MC (or just C) regions of Sup35 to replace the endogenous Sup35, with observation of cells for the [PSI+]-like phenotype upon expression (Sondheimer and Lindquist 2000; Alberti et al.2009). Thus, we had proved Swi1 can be a prion, the first of several identified prion proteins involved in global transcriptional regulation of gene expression. Defining the prion domain of Swi1 Dividing the Swi1 protein based on amino-acid composition offered three distinct regions (Fig. 1A). The amino-terminal N region was rich in asparagine residues, the middle Q region was rich in glutamine residues and the carboxyl-terminal C region previously mentioned was enriched in neither. Given that overexpression of the C region of Swi1 was able to restore Swi1 function in either deletion or prion contexts, we demonstrated that the C region contains the functional domain and that the N and Q regions were basically dispensable for SWI/SNF function (Du et al.2010). Figure 1. View largeDownload slide A schematic diagram showing Swi1 protein organization. (A) The Swi1 protein consists of three regions. The N region is highly enriched in asparagine (N) residues, holds the prion domain (PrD) and can form fibrils to seed [SWI+] formation (Du et al.2010). The middle Q region is rich in glutamine (Q) residues and modulates the aggregation pattern of the N region and Swi1 functions. The C-terminal located C region harbors the functional domain of Swi1. (B) The sequence of the N region is shown. The extreme N-terminal region, Swi11–38—shown to be able to stably transmit the prion confirmation in the absence of full-length Swi1—is underlined in black (Crow, Du and Li 2011). A reported amyloidogenic region, Swi1239–259, whose role in prionogenesis has not been tested, is also underlined (in green) (Sant’Anna et al.2016). Asparagine and glutamine residues are highlighted in red and blue, respectively. Figure 1. View largeDownload slide A schematic diagram showing Swi1 protein organization. (A) The Swi1 protein consists of three regions. The N region is highly enriched in asparagine (N) residues, holds the prion domain (PrD) and can form fibrils to seed [SWI+] formation (Du et al.2010). The middle Q region is rich in glutamine (Q) residues and modulates the aggregation pattern of the N region and Swi1 functions. The C-terminal located C region harbors the functional domain of Swi1. (B) The sequence of the N region is shown. The extreme N-terminal region, Swi11–38—shown to be able to stably transmit the prion confirmation in the absence of full-length Swi1—is underlined in black (Crow, Du and Li 2011). A reported amyloidogenic region, Swi1239–259, whose role in prionogenesis has not been tested, is also underlined (in green) (Sant’Anna et al.2016). Asparagine and glutamine residues are highlighted in red and blue, respectively. Expression of varying constructs of combinations of the Swi1 protein regions (N, NQ, QC, C) would elucidate which regions were sufficient and necessary for [SWI+]. Fluorescently tagged versions of N and NQ were the only constructs to exhibit aggregation in [SWI+] cells, thus the Q and C regions were not necessary for the aggregation phenotype (Du et al.2010). One aspect that was noted to be affected by the inclusion of the Q region was the typical pattern of aggregation. We speculated that this change in aggregation pattern may be due to protein interactions mediated by the Q region—such as those via the possible actin-binding domain present in this region (Du et al.2010). Also, expression of QC instead of just the C region alone demonstrated a better ability to rescue the lack of growth of swi1Δ cells on raffinose media—suggesting a role for the Q region in normal Swi1 function (Du et al.2010). Further support for the N region containing the Swi1 PrD would come from the fact that chromosomal deletion of the N region of Swi1 resulted in cells unable to maintain [SWI+] and unable to have [SWI+] cytoduced (Du et al.2010). Additionally, the recombinant N region of Swi1 formed amyloid fibrils in vitro with infectivity observed via fibril transformation experiments (Du et al.2010). Therefore, the N region includes the Swi1 PrD. To further characterize this amino-terminal PrD, truncation experiments revealed that the extreme amino-terminal of Swi1 acts as a major determinant for [SWI+]. The truncation of the N region (Swi11–323) down to Swi11–38 still conserved the ability to aggregate in [SWI+] cells and maintain and propagate [SWI+] in the absence of full-length Swi1 (Crow, Du and Li 2011). Importantly, this small region could also transmit [SWI+] back to full-length Swi1. Meanwhile, constructs not containing this extreme amino-terminal region (e.g. Swi155–327) were unable to support [SWI+] propagation. Interestingly, Swi11–38 consisted of an extremely asparagine-rich region that was also glutamine-free (Fig. 1B). Upon further inspection, smaller amino-terminal regions (down to, and including Swi11–32) were found to be able to co-aggregate with full-length Swi1 in [SWI+] cells, maintain the prion fold in the absence of the full-length protein and transmit the prion conformation back to full-length Swi1 (Valtierra, Du and Li 2017). In addition, when full-length Swi1 was overexpressed, other smaller truncations (down to, and including Swi11–28) aggregated in [SWI+] cells—although these smaller constructs could not stably maintain [SWI+] as the prion would be quickly lost upon passaging. Intriguingly, a few such small Swi1 amino-terminal truncations were capable of acting as valid PrDs to support de novo prion formation and transmission of a chimeric prion. This capability was demonstrated via the classic Sup35 assay (Sondheimer and Lindquist 2000). In this assay, Swi11–38, Swi11–32 and Sw11–31 all could recapitulate the [PSI+]-like phenotype as artificial prions ([SPS+]) when fused with the MC region of Sup35 (Valtierra, Du and Li 2017). Further work is necessary to determine the roles of the extreme amino-terminal region (∼30 amino acids) in Swi1 prion de novo formation and propagation regarding the prion-forming frequency, stabilization and interactions with other proteins. Meanwhile, another recent study utilized bioinformatics to predict and confirm that there is an additional amyloid-forming region (Swi1239–259) within the Swi1 PrD but beyond the amino-terminal region we have examined (Sant’Anna et al.2016). It remains to be determined if this region is prionogenic or contributes to [SWI+] formation and propagation events. Chaperone effects on [SWI+] A suite of chaperones in yeast provides the ability for prions to be maintained and propagate. The chaperone system composed of Hsp104, Hsp70 and Hsp40 has been shown to be essential for propagating all amyloid prions (Liebman and Chernoff 2012). To allow for one part of this chaperone system, the disaggregase, Hsp104 to bind, other chaperones (Hsp70 and Hsp40) must initially bind to the target protein (Chernova, Wilkinson and Chernoff 2017). Once bound, Hsp104 acts on prion aggregates to fragment them and, thus, generates propagons or prion seeds for passing the prion to daughter cells (Cox, Ness and Tuite 2003; Kryndushkin et al.2003). Most yeast prions are highly susceptible to Hsp104 disruption but only [PSI+] is susceptible to Hsp104 overproduction (Crow and Li 2011; Liebman and Chernoff 2012). [SWI+] cells can be readily cured through either Hsp104 inactivation through GdnHCl treatment or ectopic expression of a dominant-negative Hsp104 mutant (Du et al.2008; Valtierra, Du and Li 2017). However, like [RNQ+] and [URE3] but not [PSI+], [SWI+] was not found to be susceptible to elimination via overexpression of HSP104. Another crucial class of chaperones for yeast prions is the Hsp70s, which consists of a family of six different proteins (Ssa1, Ssa2, Ssa3, Ssa4, Ssb1, Ssb2) (Craig et al.1995). Hsp70 chaperones were shown as important modulators of [PSI+] propagation (Jung et al.2000; Jones et al.2004; Allen et al.2005). In addition to these proteins, a number of co-chaperones exist that together with the Hsp70s act as concerted machinery (Sharma and Masison 2009). These additional proteins include J-proteins and nucleotide exchange factors (NEFs). Disruptions to any of these proteins may disrupt a yeast prion's ability to be stably maintained and propagate (Sondheimer et al.2001; Kryndushkin et al.2002; Aron et al.2007; Fan et al.2007; Kryndushkin and Wickner 2007; Higurashi et al.2008; Sadlish et al.2008; Sharma and Masison 2009; Hines et al.2011). [SWI+], in particular, has been shown to be very sensitive to such disruptions. When a mutant of Ssa1, Ssa1-21 was expressed, this dominant negative variant managed to cure [SWI+] in all observed colonies (Hines et al.2011). On the other hand, the same experiment conducted with [PSI+] cells instead displayed only infrequent loss of [PSI+] (Jung et al.2000). This sensitivity of [SWI+] to perturbation of the Hsp70 system extends to its co-chaperones. Among the NEFs in yeast are Sse1 and Sse2, which are classified as Hsp110s and can function as the NEFs of Hsp70 (Dragovic et al.2006; Raviol et al.2006). In accordance to previous data showing that the presence of Sse1 was important for propagation of some other yeast prions, [SWI+] was examined for a similar dependence. Deletion of Sse1 leads to complete elimination of [SWI+], indicating reliance on Sse1 (Fan et al.2007; Kryndushkin and Wickner 2007; Hines et al.2011). Additionally, the study found that overexpression of either Sse1 or Sse2 could also destabilize [SWI+] in a 74D-694 strain. However, recent results from a separate investigation has revealed that similar Sse1 overexpression in a BY4741 strain cannot cure [SWI+]—indicating strain-specific effects (Du et al.2017). Moreover, Sse1 was shown to still function in maintaining and propagating [SWI+] as overexpression of Sse1 in the same BY4741 strain hindered curing via GdnHCl (Du et al.2017). These results indicate the sensitive role of Sse1/2 in [SWI+] maintenance and propagation and that such sensitivity may vary from strain-to-strain. [SWI+] was found to be sensitive to the overexpression of multiple different Hsp40s (J-proteins). When the J-proteins Sis1, Ydj1 or Apj1 were constitutively overexpressed from a plasmid, [SWI+] was lost in the majority of colonies via observation of Swi1 aggregation. In fact, even overexpression of just the J-domain of these J-proteins produced a similar effect. Additionally, repression of Sis1 expression was found to eliminate [SWI+] over multiple generations—likely due to an effect on [SWI+] propagation and thus indicating the need for Sis1 in propagating [SWI+] just like other prions (Sondheimer et al.2001; Aron et al.2007; Higurashi et al.2008). Meanwhile, another noteworthy interplay between [SWI+] and the J-proteins was the finding that deletion of the entirety of Ydj1 or just the carboxyl-terminal domain of Ydj1 also eliminated [SWI+]—again suggesting that this region of this protein was critical to [SWI+] propagation. Overexpression of a similar J-protein, Apj1 was able to partially rescue this loss of [SWI+]—demonstrating possible redundancy of the chaperone system (Hines et al.2011). The disruption of these select J-proteins display significant disruption of [SWI+] propagation; however, given that there are overlaps between J-protein functions in providing support for prion propagation, there may exist yeast strain-specific or [SWI+] variant-specific effects of disruption of individual J-proteins. This large combination of necessities and possible routes of destabilization indicates that [SWI+] is uniquely sensitive to perturbations of and uniquely reliant on the Hsp40/Hsp70 system. Hines and others hypothesized that this sensitivity may allow for more rapid adaptation to the environment due to being able to more quickly lose [SWI+] (Hines et al.2011). Phenotypes affected by [SWI+] Studying [SWI+] has been made possible via the multiple phenotypes that the prion confers to yeast (Fig. 2). First amongst these phenotypes was the poor growth on non-glucose carbon sources including raffinose, galactose, glycerol and sucrose. For example, [SWI+] cells grow at a significantly slower rate on raffinose media—providing a partial loss of function phenotype (Du et al.2008). Figure 2. View largeDownload slide Yeast cells harboring [SWI+] display a variety of phenotypes. Shown are major characterized phenotypes of the [SWI+] prion in yeast. Moving from left to right: by expression from a plasmid, fluorescently tagged Swi1 or a Swi1-PrD-containing fragment (e.g. NQ-YFP) aggregates in [SWI+] but is diffuse in [swi−] cells (Du et al. 2008, 2010). [SWI+]-containing cells exhibit poor growth on non-glucose carbon sources such as raffinose compared to [swi−] cells as shown (Du et al.2008). Multicellular features including flocculation, adhesive growth (observed via crystal blue staining after washing) and diploid pseudohyphae formation on SLAD (synthetic low ammonium dextrose) media are abolished in the presence of [SWI+] (Du, Zhang and Li 2015). [SWI+] cells are easily washed away in a wash assay and display enhanced mobility and an ability to migrate in flowing water in the illustrated raindrop assay (Newby and Lindquist 2017). Figure 2. View largeDownload slide Yeast cells harboring [SWI+] display a variety of phenotypes. Shown are major characterized phenotypes of the [SWI+] prion in yeast. Moving from left to right: by expression from a plasmid, fluorescently tagged Swi1 or a Swi1-PrD-containing fragment (e.g. NQ-YFP) aggregates in [SWI+] but is diffuse in [swi−] cells (Du et al. 2008, 2010). [SWI+]-containing cells exhibit poor growth on non-glucose carbon sources such as raffinose compared to [swi−] cells as shown (Du et al.2008). Multicellular features including flocculation, adhesive growth (observed via crystal blue staining after washing) and diploid pseudohyphae formation on SLAD (synthetic low ammonium dextrose) media are abolished in the presence of [SWI+] (Du, Zhang and Li 2015). [SWI+] cells are easily washed away in a wash assay and display enhanced mobility and an ability to migrate in flowing water in the illustrated raindrop assay (Newby and Lindquist 2017). In contrast, another phenotype of [SWI+], the loss of multicellular features such as flocculation, invasive growth and pseudohyphae formation provides a complete loss of function phenotype (Du, Zhang and Li 2015). [SWI+] cells can be easily observed to have abolished ability to flocculate in liquid media. A simple wash assay displays the lack of invasive growth of prion cells versus non-prion and diploids can be examined for the loss of any pseudohyphae formation. Note that in order for [swi−] cells to demonstrate the multicellular phenotypes, it may require repair of the FLO8 gene in some lab strains (e.g. 74-D694 and S288C). By taking advantage of the tight regulation of the FLO genes by Swi1, a reporter system was established by replacing the FLO1 gene with URA3 at its chromosomal locus, which allows for selection for and against [SWI+] using 5-fluroorotic acid and uracil-deficient selective media, respectively (Du et al.2017). The aggregation phenotype of [SWI+] can be observed via transformation of marker plasmids expressing Swi1 that is fluorescently tagged—e.g. Swi1-YFP or Swi1NQ-YFP. The exact aggregation pattern observed with these plasmids may vary depending on the construct utilized. For example, in [SWI+] cells and in the presence of endogenous full-length Swi1, Swi1N-YFP tends to have a large portion of the cells containing single large aggregates, Swi1NQ-YFP more frequently displays multiple small aggregates, and full-length Swi1-YFP features a mix of both types of aggregates (Du et al.2010). Numerous studies show that yeast prions can display evolutionarily advantageous traits and thus are beneficial (True and Lindquist 2000; True, Bedin and Lindquist 2004; Halfmann et al.2012a; Holmes et al.2013; Jarosz et al.2014; Chakrabortee et al.2016a). However, it has also been argued that some prions, such as [PSI+] and [URE3], are diseases of yeast due to a variety of factors including the presence of detrimental phenotypes and induction of proteins tied to the stress response (Wickner et al.2011). The phenotypes of poor growth on non-glucose carbon sources and abolishment of multicellular features both may suggest that [SWI+] is associated with a disease state. The observed instability of [SWI+] may point to the prion being an unwanted feature. However, as the conversion frequency of [SWI+] is also higher than [PSI+], the ability of [SWI+] to be easily lost or gained may possibly provide yeast with a flexibility and capacity to rapidly adapt to the environment through selection (Lancaster et al.2010; Hines et al.2011; Du et al.2017). Indeed, research demonstrates that [SWI+] may also offer beneficial, functional phenotypic adaptations. When compared to isogenic [swi−] cells, [SWI+] cells were shown to have greater resistance to the microtubule-inhibiting fungicide benomyl in certain strains—demonstrating that the [SWI+] prion can be beneficial under certain conditions (Alberti et al.2009). Although it is largely believed that multicellular features help yeast to survive poor nutrient conditions and protect cells from various stresses (Granek and Magwene 2010; Brückner and Mösch 2012), we previously speculated that under optimal growth conditions, yeast may favor the unicellular form (Du, Zhang and Li 2015). The unicellular form would provide the yeast cells the ability to freely migrate and quickly multiply and thus, conversion between [SWI+] and [swi−] would allow cells to sense and adapt to environmental changes through gain or loss of multicellular features. Indeed, recent research has shown that the loss, via [SWI+], of multicellular features allows for enhanced mobility of yeast (Fig. 2; Newby and Lindquist 2017). These cells, termed pioneers, offer possible advantages in some environmental situations. The lack of multicellular features allows for easier water-based migration of the cells as originally observed in a wash assay (Du, Zhang and Li 2015). Another water-based assay, the raindrop assay further demonstrated this fact and portrays prion cells as allowing yeast to travel with water flow and grow in new regions—providing access to additional nutrients and a corresponding boost to fitness (Newby and Lindquist 2017). This relatively new assay and pseudo-environmental phenotype provides a glimpse into the possibility of [SWI+] and other yeast prions acting as quick adaptive mechanisms. Lastly, the previously known requirement for Swi1 function for expression of the HO gene, which allows for mating type switching, creates another malleable phenotype (Stern, Jensen and Herskowitz 1984). Prionization of Swi1 in the form of [SWI+] leads to a likely decrease in HO expression and mating-type switching. As such, Newby and Lindquist reported that [SWI+] spores demonstrate an increased rate of out-crossing—mating of mother cells with non-daughter cells—compared to [swi−] spores (Newby and Lindquist 2017). This enhancement of out-crossing and the reduction of inbreeding were due to the disability of [SWI+] cells in mating-type switching and was eliminated with loss of the prion. The increased out-crossing may increase genetic variation and thus provide an advantage to prion cells in diverse environments. Additional phenotypes of [SWI+] likely remain to be uncovered since the role of Swi1 as a global transcription regulator allows for possible impact on a wide range of yeast phenotypes. To reveal such novel phenotypes, a genomics-focused approach may be appropriate. For example, RNA sequencing (RNA-seq) could reveal differences between [SWI+], [swi−] and swi1Δ cells—providing a clearer picture of the transcriptional impact of the prion. Moreover, pairing such methodology with a systematic phenotypic assay would provide a strong probability of identifying additional [SWI+] phenotypes that could be deleterious or beneficial in nature. Regulation of multicellular features by yeast prions Following the discovery of [SWI+], additional studies identified several new yeast prions including [OCT+], [GAR+], [MOD+], [NUP100+] and [MOT3+] (Brown and Lindquist 2009; Patel, Gavin-Smyth and Liebman 2009; Suzuki, Shimazu and Tanaka 2012; Halfmann et al.2012b; Holmes et al.2013). The protein determinants for these prions—Cyc8, Pma1/Std1, Mod5, Nup100 and Mot3, respectively—feature additional transcriptional regulators (Cyc8 and Mot3); the fact that several transcriptional regulators could act as prions has been extensively discussed (Alberti et al.2009; Du 2011; Du, Zhang and Li 2015). Of particular importance was the possibility of prion–prion interactions in concert with transcriptional interactions to regulate key yeast processes. Along with Swi1, the yeast prion proteins of Cyc8, Mot3 and Ure2 (via regulation of Gln3) have noted regulatory targets involving multicellular features of yeast including flocculation, pseudohyphae development and invasive growth (Barrales, Jimenez and Ibeas 2008; Barrales et al.2012; Holmes et al.2013). As the yeast SWI/SNF complex regulates the transcription of approximately 6% of the genome by one estimation (Sudarsanam et al.2000), prionization of Swi1 was hypothesized to greatly affect the transcriptional profile of cells and thus the phenotypes observed. The regulation of the flocculin (FLO) genes by SWI/SNF, and thus, Swi1, provided a mechanism for [SWI+] to abolish the aforementioned multicellular features. Indeed, this has been shown to occur in the presence of [SWI+] (Fig. 3; Du, Zhang and Li 2015). Interestingly, other FLO gene transcriptional activators—such as Mss11 and Sap30—co-aggregate with Swi1 and are titrated by [SWI+] (Du, Zhang and Li 2015), causing abolishment instead of reduction of multicellular features. This setup alone makes for an elegant regulation of phenotypes that can be critical to yeast survival. Figure 3. View largeDownload slide Regulation of multicellular features by prion proteins in yeast. The yeast prion proteins of Swi1, Cyc8 and Mot3 are regulators of FLO gene expression. In the non-prion state, Swi1 (as a component of the SWI/SNF chromatin remodeling complex) promotes FLO gene expression; Mot3 and Cyc8 (subunit of the Cyc8-Tup1 co-repressor complex) act as transcriptional repressors of FLO genes (Barrales et al.2012; Holmes et al.2013). The [MOT3+] prion promotes multicellular features by enhancing FLO gene expression, whereas [SWI+] abolishes FLO gene expression and thus eliminates multicellular features (Holmes et al.2013; Du, Zhang and Li 2015). The Cyc8 prion ([OCT+]) would be predicted to remove a source of repression and, thus, increase FLO gene expression. Yeast can harbor multiple prions and the interaction among the three prions may intricately modulate FLO gene expression. Figure 3. View largeDownload slide Regulation of multicellular features by prion proteins in yeast. The yeast prion proteins of Swi1, Cyc8 and Mot3 are regulators of FLO gene expression. In the non-prion state, Swi1 (as a component of the SWI/SNF chromatin remodeling complex) promotes FLO gene expression; Mot3 and Cyc8 (subunit of the Cyc8-Tup1 co-repressor complex) act as transcriptional repressors of FLO genes (Barrales et al.2012; Holmes et al.2013). The [MOT3+] prion promotes multicellular features by enhancing FLO gene expression, whereas [SWI+] abolishes FLO gene expression and thus eliminates multicellular features (Holmes et al.2013; Du, Zhang and Li 2015). The Cyc8 prion ([OCT+]) would be predicted to remove a source of repression and, thus, increase FLO gene expression. Yeast can harbor multiple prions and the interaction among the three prions may intricately modulate FLO gene expression. Compounding this [SWI+]-driven regulation of FLO gene expression and multicellular features was the additional regulation of the same features or genes by Mot3. A prior investigation of Mot3 demonstrated the ability of yeast to gain multicellular features such as biofilm formation and invasive growth via prionization of Mot3 ([MOT3+]) (Holmes et al.2013). This event may then act as a boost to the fitness of the [MOT3+] yeast—demonstrating the prion to act in a functional fashion rather than perpetuating a disease-state. Interestingly, this regulation of yeast multicellularity by [MOT3+] exists in noted opposition to [SWI+]. Mot3 normally represses FLO gene expression, while Swi1 promotes FLO gene expression. Prionization de-represses expression in the case of [MOT3+], while [SWI+] un-induces expression (Fig. 3). A layered regulation of yeast multicellularity was thus identified via the studies of these two prions. To further complicate the regulation of these important but limited phenotypes, the protein determinant of [OCT+], Cyc8 enters the ring (Patel, Gavin-Smyth and Liebman 2009). The normal function of Cyc8 is transcriptional control—including acting as an inhibitor of FLO gene expression in conjunction with Tup1 (Fig. 3; Barrales, Jimenez and Ibeas 2008). Thus, one additional layer of regulation may exist where the non-prion form of Cyc8 inhibits FLO gene expression and its prionization disinhibits expression (Fig. 3). It should be noted that there are multiple FLO genes and each gene may be differentially targeted by the yeast prion proteins such as Swi1, Mot3 and Cyc8 and that each gene may have variable roles in the multitude of multicellular phenotypes—increasing the complexity of regulation. Additionally, other yeast proteins capable of forming prions may also play a role in the regulation of these particular genes—or other overlapping targets for unrelated phenotypes. Furthermore, the possibility for yeast to harbor multiple of the FLO gene-regulating prions at once provides an opportunity for intricate regulation. Combined with probable prion–prion interactions between [SWI+], [MOT3+] and [OCT+] and possibly [URE3], a significant and multi-layered transcriptional network likely exists that remains to be fully uncovered. Characterizing prion–prion interactions of [SWI+] It is well-documented that a single yeast cell can harbor more than one prion element and that when two prions co-exist, they influence not only each other's de novo appearance but also propagation (Derkatch et al. 1997, 2001, 2004). Investigation of prion–prion interactions—such as those examined in the yeast system—has particular significance as it may aid in uncovering pathological mechanisms in neurological disorders where interactions between amyloidogenic and/or prion-like proteins are highlighted (Clinton et al.2010; Ono et al.2012; Guo et al.2013). Saccharomyces cerevisiae has provided ample opportunity to investigate interactions between different endogenous prions, various prion strains, as well as exogenously expressed prion-like proteins (Meriin et al.2002). As noted earlier, overexpression of Swi1 had been shown to induce the appearance of [PSI+] (Derkatch et al.2001; Du et al.2008). These data highlighted the likelihood that [SWI+] would similarly be shown to be capable of inducing [PSI+]. Indeed, further study revealed that [SWI+] increases the formation rate of both [PSI+] and [RNQ+] and that a cross-seeding mechanism was likely responsible (Du and Li 2014). The ability for a yeast cell to contain at least three distinct prions—[PSI+], [RNQ+] and [SWI+]—was also documented. However, colocalization of these prion proteins was found to vary based on the maturity of the aggregates with colocalization (and thus interactions) being restricted primarily to the early, or initiation, stage of prion formation (Du and Li 2014). In addition, [PSI+] and [RNQ+] have been demonstrated to affect the formation rate of [SWI+]. Utilizing the FLOpr-URA3 reporter system, the spontaneous de novo formation rate of [SWI+] in non-prion cells was found to be approximately 5 × 10−4 in the S288C lab strain and 4 × 10−5 in the 74D-694 lab strain (Du et al.2017). However, the presence of [PSI+] or [RNQ+] was shown to increase this de novo formation rate by a factor of 100 or 10, respectively (Du et al.2017). These increases as well as the previously discussed reports demonstrate that [PSI+], [RNQ+] and [SWI+] can mutually promote the formation of one another. An additional example of prion–prion interaction with [SWI+] and [RNQ+] was reported in the form of [NSI+], a non-Mendelian genetic factor exhibiting a suppression of nonsense mutations in yeast strains with a deleted or modified Sup35 N-terminal domain (Saifitdinova et al.2010). Initially characterized as an element with many prion qualities, the protein determinant was later reported to consist of an interaction between [SWI+] and [RNQ+] rather than a novel prion protein in a specific yeast strain background (Nizhnikov et al.2016). Whereas [SWI+] on its own recapitulated a mild form of the [NSI+] nonsense suppression via reduction of Sup45 expression, [RNQ+] enhanced this phenotype further thus creating what was previously identified as the [NSI+] phenotype (Nizhnikov et al.2016). Further studies may reveal additional combinatorial phenotypes between [SWI+] and other yeast prions—particularly possible with the aforementioned trifecta of FLO gene regulators. The possibility of combinations of the yeast prions that may help govern yeast multicellularity—[SWI+], [MOT3+] and [OCT+]—could lead to an agile adaptive mechanism. Moreover, interactions between these prions may inherent biases towards certain phenotypes while maintaining what has been previously described as a ‘bet-hedging’ system. The possibility of the development of intermediate or mixed phenotypes on an individual or population level, respectively, also exists. Such phenotypes would better suit the wide range of prospective environmental conditions. CONCLUDING REMARKS Through the discovery, characterization, and further investigation of the Swi1 prion, [SWI+], much insight has been gained on the prion biology. The identification of [SWI+] and Swi1 as its prion determinant in yeast was the first identification of a global transcriptional regulator being able to form a prion (Du et al.2008). A small, asparagine-rich extreme amino-terminal region has been described as the major determinant of [SWI+], and the ability of this region to propagate and maintain [SWI+] is notable (Crow, Du and Li 2011; Valtierra, Du and Li 2017). [SWI+] has also displayed important and varied interplay with other yeast prions including [PSI+] and [RNQ+]—developing the knowledge regarding prion–prion interactions and formation of prions (Du and Li 2014; Nizhnikov et al.2016; Du et al.2017). And perhaps most significant from an evolutionary standpoint, [SWI+] has been demonstrated as a crucial regulator of yeast multicellularity as part of a yet-to-be fully understood network of multiple yeast prions and other proteins (Du, Zhang and Li 2015). Additionally, as a limited number of conditions have been investigated for [SWI+] conferring a selective advantage, there may exist other conditions where the prion demonstrates to be advantageous. Expanding beyond the contributions of [SWI+] research to the understanding of yeast prions and prion networks, the human SWI/SNF complex (also known as the BAF complex) includes components that may be similarly prone to aggregation—perhaps of a prion-like nature—as Swi1. The highly conserved nature of the SWI/SNF chromatin remodeling complex through eukaryotes makes investigation of the human BAF complex tantamount. The likelihood that the BAF complex harbors aggregating proteins proves enticing as a possible target for disease treatment. Human diseases ranging from numerous types of cancers to serious neurodevelopmental disorders have correlations to the erroneous or lost function of the BAF complex (Son and Crabtree 2014; Kadoch and Crabtree 2015). Interestingly, recent research has shown that fusion of the prion-like domain of the EWS protein with the FLI1 transcription factor can act to change the genes targeted by the BAF complex in cancer (Boulay et al.2017). Perhaps direct aggregation—maybe in a prion-like fashion—of BAF complex proteins contributes to the multitude of pathological avenues in these diseases. Acknowledgements The authors would like to dedicate this article to Susan Lindquist, an excellent mentor, outstanding researcher and inspiring leader in the yeast prion field. Her many important contributions to science will be remembered. FUNDING This work is supported by a grant from the U.S. National Institutes of Health (R01GM110045) to LL. Conflicts of interest. None declare. 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FEMS Yeast ResearchOxford University Press

Published: May 25, 2018

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