doi: 10.1038/s44319-024-00273-9pmid: 39322742
Can the scientific literature act as a guide to how social media might self-regulate?[graphic not available: see fulltext]
doi: 10.1038/s44319-024-00268-6pmid: 39313724
Michael Bronstein outlines his vision for the new Aithyra Institute, which aims to transform biological sciences using AI, with a focus on developing novel approaches to data collection, model training, and hypothesis generation to advance research and improve human health.[graphic not available: see fulltext]
Liu, Jianheng Fox; Jaffrey, Samie R
doi: 10.1038/s44319-024-00263-xpmid: 39304776
N1-methyladenosine (m1A) is a very rare RNA modification in mammalian mRNA, which occurs in sequences resembling the T-loop of tRNAs and may not have significant effects on gene expression. A new study in this issue now reports that m1A is abundant and dynamic in the 3′UTR of mRNAs of dinoflagellates, and could have an important role in post-transcriptional gene expression regulation in these organisms.
Sager, Rebecca A; Backe, Sarah J; Dunn, Diana M; Heritz, Jennifer A; Ahanin, Elham; Dushukyan, Natela; Panaretou, Barry; Bratslavsky, Gennady; Woodford, Mark R; Bourboulia, Dimitra; Mollapour, Mehdi
doi: 10.1038/s44319-024-00250-2pmid: 39304777
The serine/threonine protein phosphatase 5 (PP5) regulates hormone and stress-induced signaling networks. Unlike other phosphoprotein phosphatases, PP5 contains both regulatory and catalytic domains and is further regulated through post-translational modifications (PTMs). Here we identify that SUMOylation of K430 in the catalytic domain of PP5 regulates phosphatase activity. Additionally, phosphorylation of PP5-T362 is pre-requisite for SUMOylation, suggesting the ordered addition of PTMs regulates PP5 function in cells. Using the glucocorticoid receptor, a well known substrate for PP5, we demonstrate that SUMOylation results in substrate release from PP5. We harness this information to create a non-SUMOylatable K430R mutant as a ‘substrate trap’ and globally identified novel PP5 substrate candidates. Lastly, we generated a consensus dephosphorylation motif using known substrates, and verified its presence in the new candidate substrates. This study unravels the impact of cross talk of SUMOylation and phosphorylation on PP5 phosphatase activity and substrate release in cells.
Li, Chongping; Li, Ying; Guo, Jia; Wang, Yuci; Shi, Xiaoyan; Zhang, Yangyi; Liang, Nan; Ma, Honghui; Yuan, Jie; Xu, Jiawei; Chen, Hao
doi: 10.1038/s44319-024-00234-2pmid: 39223385
Dinoflagellates, a class of unicellular eukaryotic phytoplankton, exhibit minimal transcriptional regulation, representing a unique model for exploring gene expression. The biosynthesis, distribution, regulation, and function of mRNA N1-methyladenosine (m1A) remain controversial due to its limited presence in typical eukaryotic mRNA. This study provides a comprehensive map of m1A in dinoflagellate mRNA and shows that m1A, rather than N6-methyladenosine (m6A), is the most prevalent internal mRNA modification in various dinoflagellate species, with an asymmetric distribution along mature transcripts. In Amphidinium carterae, we identify 6549 m1A sites characterized by a non-tRNA T-loop-like sequence motif within the transcripts of 3196 genes, many of which are involved in regulating carbon and nitrogen metabolism. Enriched within 3′UTRs, dinoflagellate mRNA m1A levels negatively correlate with translation efficiency. Nitrogen depletion further decreases mRNA m1A levels. Our data suggest that distinctive patterns of m1A modification might influence the expression of metabolism-related genes through translational control.
Nunes, Ivanéia V; Breitenbach, Luisa; Pawusch, Sarah; Eigenbrod, Tatjana; Ananth, Swetha; Schad, Paulina; Fackler, Oliver T; Butter, Falk; Dalpke, Alexander H; Chen, Lan-Sun
doi: 10.1038/s44319-024-00281-9pmid: 39363059
TLR8 senses single-stranded RNA (ssRNA) fragments, processed via cleavage by ribonuclease (RNase) T2 and RNase A family members. Processing by these RNases releases uridines and purine-terminated residues resulting in TLR8 activation. Monocytes show high expression of RNase 6, yet this RNase has not been analyzed for its physiological contribution to the recognition of bacterial RNA by TLR8. Here, we show a role for RNase 6 in TLR8 activation. BLaER1 cells, transdifferentiated into monocyte-like cells, as well as primary monocytes deficient for RNASE6 show a dampened TLR8-dependent response upon stimulation with isolated bacterial RNA (bRNA) and also upon infection with live bacteria. Pretreatment of bacterial RNA with recombinant RNase 6 generates fragments that induce TLR8 stimulation in RNase 6 knockout cells. 2’O-RNA methyl modification, when introduced at the first uridine in the UA dinucleotide, impairs processing by RNase 6 and dampens TLR8 stimulation. In summary, our data show that RNase 6 processes bacterial RNA and generates uridine-terminated breakdown products that activate TLR8.
Libert, Maxime; Quiquempoix, Sophie; Fain, Jean S; Pyr dit Ruys, Sébastien; Haidar, Malak; Wulleman, Margaux; Herinckx, Gaëtan; Vertommen, Didier; Bouchart, Christelle; Arsenijevic, Tatjana; Van Laethem, Jean-Luc; Jacquemin, Patrick
doi: 10.1038/s44319-024-00284-6pmid: 39390257
Stress granules (SG) are membraneless ribonucleoprotein-based cytoplasmic organelles that assemble in response to stress. Their formation is often associated with an almost global suppression of translation, and the aberrant assembly or disassembly of these granules has pathological implications in neurodegeneration and cancer. In cancer, and particularly in the presence of oncogenic KRAS mutations, in vivo studies concluded that SG increase the resistance of cancer cells to stress. Hence, SG have recently been considered a promising target for therapy. Here, starting from our observations that genes coding for SG proteins are stimulated during development of pancreatic ductal adenocarcinoma, we analyze the formation of SG during tumorigenesis. We resort to in vitro, in vivo and in silico approaches, using mouse models, human samples and human data. Our analyses do not support that SG are formed during tumorigenesis of KRAS-driven cancers, at least that their presence is not universal, leading us to propose that caution is required before considering SG as therapeutic targets.
Sun, Junqing; Kuai, Lu; Zhang, Lei; Xie, Yufeng; Zhang, Yanfang; Li, Yan; Peng, Qi; Shao, Yuekun; Yang, Qiuxian; Tian, Wen-Xia; Zhu, Junhao; Qi, Jianxun; Shi, Yi; Deng, Tao; Gao, George F
doi: 10.1038/s44319-024-00208-4pmid: 39026012
Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals.
Ulferts, Svenja; Grosse, Robert
doi: 10.1038/s44319-024-00274-8pmid: 39317734
The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.
Chen, Yuting; Liu, Zhaojie; Zhang, Yi; Ye, Miao; Chen, Yingcong; Gao, Jianhua; Song, Juan; Yang, Huan; Wu, Choufei; Yao, Weijing; Bai, Xue; Fan, Mingzhu; Feng, Shan; Wang, Yigang; Zhang, Liqin; Ge, Liang; Feng, Du; Yi, Cong
Showing 1 to 10 of 31 Articles
CCT2 serves as an aggrephagy receptor that plays a crucial role in the clearance of solid aggregates, yet the underlying molecular mechanisms by which CCT2 regulates solid aggrephagy are not fully understood. Here we report that the binding of Cct2 to Atg8 is governed by two distinct regulatory mechanisms: Atg1-mediated Cct2 phosphorylation and the interaction between Cct2 and Atg11. Atg1 phosphorylates Cct2 at Ser412 and Ser470, and disruption of these phosphorylation sites impairs solid aggrephagy by hindering Cct2-Atg8 binding. Additionally, we observe that Atg11, an adaptor protein involved in selective autophagy, directly associates with Cct2 through its CC4 domain. Deficiency in this interaction significantly weakens the association of Cct2 with Atg8. The requirement of Atg1-mediated Cct2 phosphorylation and of Atg11 for CCT2-LC3C binding and subsequent aggrephagy is conserved in mammalian cells. These findings provide insights into the crucial roles of Atg1-mediated Cct2 phosphorylation and Atg11-Cct2 binding as key mediators governing the interaction between Cct2 and Atg8 during the process of solid aggrephagy.