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Myeloid FtH Regulates Macrophage Response to Kidney Injury by Modulating Snca and Ferroptosis. 髓质 FtH 通过调节 Snca 和铁凋亡调节巨噬细胞对肾损伤的反应
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.25.645219
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary Miller, Yanfeng Zhang, Laura Volpicelli-Daley, Lauren Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, József Balla, Christian Faul, Abolfazl Zarjou
{"title":"Myeloid FtH Regulates Macrophage Response to Kidney Injury by Modulating Snca and Ferroptosis.","authors":"Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary Miller, Yanfeng Zhang, Laura Volpicelli-Daley, Lauren Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, József Balla, Christian Faul, Abolfazl Zarjou","doi":"10.1101/2025.03.25.645219","DOIUrl":"https://doi.org/10.1101/2025.03.25.645219","url":null,"abstract":"<p><p>This study explored the role of myeloid ferritin heavy chain (FtH) in coordinating kidney iron trafficking in health and disease. Synuclein-α (Snca) was the sole iron-binding protein upregulated in response to myeloid FtH deletion (FtH <sup>Δ/Δ</sup> ). Following kidney injury, FtH <sup>Δ/Δ</sup> mice showed worsened kidney function. Transcriptome analysis revealed coupling of FtH deficiency with ferroptosis activation, a regulated cell death associated with iron accumulation. Adverse effects of ferroptosis were evidenced by upregulation of ferroptosis-related genes, increased oxidative stress markers, and significant iron deposition in kidney tissues. This iron buildup in FtH <sup>Δ/Δ</sup> kidneys stemmed from macrophage reprogramming into an iron-recycling phenotype, driven by Spic induction. Mechanistically, we establish that monomeric Snca functions as a ferrireductase catalyst, intensifying oxidative stress and triggering ferroptosis. Additionally, Snca accumulates in kidney diseases distinguished by leukocyte expansion across species. These findings position myeloid FtH as a pivotal orchestrator of the FtH-Snca-Spic axis driving macrophage reprogramming and kidney injury.</p><p><strong>Highlights: </strong>Myeloid FtH deficiency drives kidney injury via activation of ferroptosisMΦ FtH deficiency induces Snca, linking iron dysregulation to MΦ function and response to kidney injuryFerrireductase activity of monomeric Snca augments oxidative stress, promoting lipid peroxidation and ferroptosis.</p><p><strong>In brief: </strong>MΦ FtH modulates Snca and Spic to coordinate the injury response, linking iron trafficking to ferroptosis-induced kidney injury.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Golgi Rim is a Precise Tetraplex of Golgin Proteins that Can Self-Assemble into Filamentous Bands. 高尔基体边缘是高尔基蛋白的精确四联体,可以自我组装成丝状带。
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.27.645134
Maohan Su, Abhijith Radhakrishnan, You Yan, Yuan Tian, Hong Zheng, Ons M'Saad, Morven Graham, Jeff Coleman, Jean N D Goder, Xinran Liu, Yongdeng Zhang, Joerg Bewersdorf, James E Rothman
{"title":"The Golgi Rim is a Precise Tetraplex of Golgin Proteins that Can Self-Assemble into Filamentous Bands.","authors":"Maohan Su, Abhijith Radhakrishnan, You Yan, Yuan Tian, Hong Zheng, Ons M'Saad, Morven Graham, Jeff Coleman, Jean N D Goder, Xinran Liu, Yongdeng Zhang, Joerg Bewersdorf, James E Rothman","doi":"10.1101/2025.03.27.645134","DOIUrl":"https://doi.org/10.1101/2025.03.27.645134","url":null,"abstract":"<p><p>Golgin proteins have long been suspected to be organizers of the Golgi stack. Using three-dimensional super-resolution microscopy, we comprehensively localize the human golgin family at the rim of the Golgi apparatus at 10-20 nm resolution <i>in situ</i> . Unexpectedly, we find that the golgins are precisely organized into a tetraplex with four discrete layers, each containing a specific set of rim golgins. We observe no golgins inside the stack between its membrane-bound cisternae. Biochemically characterizing most of the golgins as isolated proteins, we find that they form anti-parallel dimers and further self-assemble into bands of multi-micron-long filaments. Based on our findings, we propose an \"outside-in\" physical model, the Golgin Organizer Hypothesis, in which the Golgi stack of cisternae and its overall ribbon morphology directly result from bending circumferential bands of rim golgin filaments onto a membrane surface, explaining stack formation without the need for special \"stacking proteins.\"</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Uncovering the electrical synapse proteome in retinal neurons via in vivo proximity labeling. 通过体内接近标记揭示视网膜神经元的电突触蛋白质组。
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2024.11.26.625481
Stephan Tetenborg, Eyad Shihabeddin, Elizebeth Olive Akansha Manoj Kumar, Crystal Sigulinsky, Karin Dedek, Ya-Ping Lin, Fabio Echeverry, Hannah Hoff, Alberto Pereda, Bryan William Jones, Christophe Ribelayga, Klaus Ebnet, Ken Matsuura, John O'Brien
{"title":"Uncovering the electrical synapse proteome in retinal neurons via in vivo proximity labeling.","authors":"Stephan Tetenborg, Eyad Shihabeddin, Elizebeth Olive Akansha Manoj Kumar, Crystal Sigulinsky, Karin Dedek, Ya-Ping Lin, Fabio Echeverry, Hannah Hoff, Alberto Pereda, Bryan William Jones, Christophe Ribelayga, Klaus Ebnet, Ken Matsuura, John O'Brien","doi":"10.1101/2024.11.26.625481","DOIUrl":"10.1101/2024.11.26.625481","url":null,"abstract":"<p><p>Electrical synapses containing Connexin 36 (Cx36) represent the main means for communication in the mammalian nervous system. However, little is known about the protein complexes that constitute these synapses. In the present study, we applied different BioID strategies to screen the interactomes of Connexin 36 the major neuronal connexin and its zebrafish orthologue Cx35b in retinal neurons. For in vivo proximity labeling in mice, we took advantage of the Cx36-EGFP strain and expressed a GFP-nanobody-TurboID fusion construct selectively in AII amacrine cells. For in vivo BioID in zebrafish, we generated a transgenic line expressing a Cx35b-TurboID fusion under control of the Cx35b promoter. Both strategies allowed us to capture a plethora of molecules that were associated with electrical synapses and showed a high degree of evolutionary conservation in the proteomes of both species. Besides known interactors of Cx36 such as ZO-1 and ZO-2 we have identified more than 50 new proteins, such as scaffold proteins, adhesion molecules and regulators of the cytoskeleton. Moreover, we determined the subcellular localization of these proteins in AII amacrine and tested potential binding interactions with Cx36. Amongst these new interactors, we identified signal induced proliferation associated 1 like 3 (SIPA1L3), a protein that has been implicated in cell junction formation and cell polarity as a new scaffold of electrical synapses. Interestingly, SIPA1L3 was able to interact with ZO-1, ZO-2 and Cx36, suggesting a pivotal role in electrical synapse function. In summary, our study provides the first detailed view of the electrical synapse proteome in retinal neurons, which is likely to apply to electrical synapses elsewhere.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cell Function Graphics: TOGGLE delineates fate and function within individual cell types via single-cell transcriptomics.
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.01.01.631041
Junpeng Chen, Zhouweiyu Chen, Tianda Sun, Eric Jiang, Kaiqing Liu, Yibing Nong, Tao Yuan, Charles C Dai, Yexing Yan, Jinwen Ge, Haihui Wu, Tong Yang, Shanshan Wang, Zixiang Su, Tian Song, Ahmed Abdelbsset-Ismail, You Li, Changping Li, Richa A Singhal, Kailin Yang, Lu Cai, Alex P Carll
{"title":"Cell Function Graphics: TOGGLE delineates fate and function within individual cell types via single-cell transcriptomics.","authors":"Junpeng Chen, Zhouweiyu Chen, Tianda Sun, Eric Jiang, Kaiqing Liu, Yibing Nong, Tao Yuan, Charles C Dai, Yexing Yan, Jinwen Ge, Haihui Wu, Tong Yang, Shanshan Wang, Zixiang Su, Tian Song, Ahmed Abdelbsset-Ismail, You Li, Changping Li, Richa A Singhal, Kailin Yang, Lu Cai, Alex P Carll","doi":"10.1101/2025.01.01.631041","DOIUrl":"10.1101/2025.01.01.631041","url":null,"abstract":"<p><p>Functional RNA plays a crucial role in regulating cellular processes throughout the life cycle of a cell. Identifying functional changes at each stage, from inception to development to maturation, functional execution, and eventual death or pathological transformation, often requires systematic comparisons of functional expression across cell populations. However, because cells of the same type often exhibit similar gene expression patterns regardless of function or fate, it is challenging to distinguish the stages of cellular fate or functional states within the same cell type, which also limits our understanding of cellular memory. Cells of the same type that share structural and gene expression similarities but originate from different regions and perform slightly distinct functions often retain unique epigenetic memory signatures. Although RNA serves as a key executor of fundamental cellular functions, its high expression similarity among cells of the same type limits its ability to distinguish functional heterogeneity. To overcome this challenge, we developed TOGGLE, utilizing higher-resolution analytical methods to uncover functional diversity at the cellular level. Then we based on TOGGLE developed an innovative Graph Diffusion Functional Map, which can significantly reduce noise, thereby more clearly displaying the functional grouping of RNA and enabling the capture of more subtle functional differences in high-dimensional data. Ultimately, this method effectively removes the influence of baseline functions from classification criteria and identifies key trajectories of cell fate determination.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Learning stochastic reaction-diffusion models from limited data using spatiotemporal features.
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2024.10.02.616367
Bedri Abubaker-Sharif, Tatsat Banerjee, Peter N Devreotes, Pablo A Iglesias
{"title":"Learning stochastic reaction-diffusion models from limited data using spatiotemporal features.","authors":"Bedri Abubaker-Sharif, Tatsat Banerjee, Peter N Devreotes, Pablo A Iglesias","doi":"10.1101/2024.10.02.616367","DOIUrl":"10.1101/2024.10.02.616367","url":null,"abstract":"<p><p>Pattern-forming stochastic systems arise throughout biology, with dynamic molecular waves observed in biochemical networks regulating critical cellular processes. Modeling these reaction-diffusion systems using handcrafted stochastic partial differential equations (PDEs) requires extensive trial-and-error tuning. Data-driven approaches for improved modeling are needed but have been hindered by data scarcity and noise. Here, we present a solution to the inverse problem of learning stochastic reaction-diffusion models from limited data by optimizing two spatiotemporal features: (1) stochastic dynamics and (2) spatiotemporal patterns. Combined with sparsity enforcement, this method identifies novel activator-inhibitor models with interpretable structure. We demonstrate robust learning from simulations of excitable systems with varying data scarcity, as well as noisy live-cell imaging data with low temporal resolution and a single observed biomolecule. This generalizable approach to learning governing stochastic PDEs enhances our ability to model and understand complex spatiotemporal systems from limited, real-world data.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction.
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.28.645120
Valerie van Weperen, Jonathan D Hoang, Neil Jani, Karim Atmani, Christopher A Chan, Kuan Cao, Shail Avasthi, Zulfiqar A Lokhandwala, Maryam Emamimeybodi, Marmar Vaseghi
{"title":"Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction.","authors":"Valerie van Weperen, Jonathan D Hoang, Neil Jani, Karim Atmani, Christopher A Chan, Kuan Cao, Shail Avasthi, Zulfiqar A Lokhandwala, Maryam Emamimeybodi, Marmar Vaseghi","doi":"10.1101/2025.03.28.645120","DOIUrl":"https://doi.org/10.1101/2025.03.28.645120","url":null,"abstract":"<p><p>After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature.
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.27.641500
Victoria S Marshe, John F Tuddenham, Kevin Chen, Rebecca Chiu, Verena C Haage, Yiyi Ma, Annie J Lee, Neil A Shneider, Julian P Agin-Liebes, Roy N Alcalay, Andrew F Teich, Peter Canoll, Claire S Riley, Dirk Keene, Julie A Schneider, David A Bennett, Vilas Menon, Mariko Taga, Hans-Ulrich Klein, Marta Olah, Masashi Fujita, Ya Zhang, Peter A Sims, Philip L De Jager
{"title":"A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature.","authors":"Victoria S Marshe, John F Tuddenham, Kevin Chen, Rebecca Chiu, Verena C Haage, Yiyi Ma, Annie J Lee, Neil A Shneider, Julian P Agin-Liebes, Roy N Alcalay, Andrew F Teich, Peter Canoll, Claire S Riley, Dirk Keene, Julie A Schneider, David A Bennett, Vilas Menon, Mariko Taga, Hans-Ulrich Klein, Marta Olah, Masashi Fujita, Ya Zhang, Peter A Sims, Philip L De Jager","doi":"10.1101/2025.03.27.641500","DOIUrl":"https://doi.org/10.1101/2025.03.27.641500","url":null,"abstract":"<p><p>Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.g., metabolism, phagocytosis, antigen presentation, inflammatory signaling, disease-associated states). Using external datasets, we evaluated the aspects of microglial phenotypes that are encapsulated in various <i>in vitro</i> and <i>in vivo</i> microglia models and identified and replicated the role of two factors in human postmortem tissue of Alzheimer's disease (AD). Further, we derived a complex network of transcriptional regulators for all factors, including regulators of an AD-related factor enriched for the mouse disease-associated microglia 2 (DAM2) signature: <i>ARID5B</i> , <i>CEBPA</i> , <i>MITF</i> , and <i>PPARG</i> . We replicated the role of these four regulators in the AD-related factor and then designed a multiplexed MERFISH panel to assess our microglial factors using spatial transcriptomics. We find that, unlike cells with high expression of the interferon-response factor, cells with high expression of the AD DAM2-like factor are widely distributed in neocortical tissue. We thus propose a novel analytic framework that provides a taxonomic approach for microglia that is more biologically interpretable and use it to uncover new therapeutic targets for AD.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genome-wide dynamic nascent transcript profiles reveal that most paused RNA polymerases terminate. 全基因组动态新生转录本图谱显示,大多数暂停的 RNA 聚合酶都会终止。
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.27.645809
Rudradeep Mukherjee, Michael J Guertin
{"title":"Genome-wide dynamic nascent transcript profiles reveal that most paused RNA polymerases terminate.","authors":"Rudradeep Mukherjee, Michael J Guertin","doi":"10.1101/2025.03.27.645809","DOIUrl":"https://doi.org/10.1101/2025.03.27.645809","url":null,"abstract":"<p><p>We present a simple model for analyzing and interpreting data from kinetic experiments that measure engaged RNA polymerase occupancy. The framework represents the densities of nascent transcripts within the pause region and the gene body as steady-state values determined by four key transcriptional processes: initiation, pause release, premature termination, and elongation. We validate the model's predictions using data from experiments that rapidly inhibit initiation and pause release. The model successfully classified factors based on the steps in early transcription that they regulate, confirming TBP and ZNF143 as initiation factors and HSF and GR as pause release factors. We found that most paused polymerases terminate and paused polymerases are short-lived with half lives less than a minute. We make this model available as software to serve as a quantitative tool for determining the kinetic mechanisms of transcriptional regulation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SMC5/6-Mediated Plasmid Silencing is Directed by SIMC1-SLF2 and Antagonized by LT. SMC5/6介导的质粒沉默由SIMC1-SLF2引导,并被LT拮抗。
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.27.645818
Martina Oravcová, Minghua Nie, Takanori Otomo, Michael N Boddy
{"title":"SMC5/6-Mediated Plasmid Silencing is Directed by SIMC1-SLF2 and Antagonized by LT.","authors":"Martina Oravcová, Minghua Nie, Takanori Otomo, Michael N Boddy","doi":"10.1101/2025.03.27.645818","DOIUrl":"https://doi.org/10.1101/2025.03.27.645818","url":null,"abstract":"<p><p>SMC5/6 is unique amongst the Structural Maintenance of Chromosomes (SMC) complexes in its ability to repress transcription from extrachromosomal circular DNA (ecDNA), including viral genomes and plasmids. Previously, we showed that human SMC5/6 is regulated by two mutually exclusive subcomplexes-SIMC1-SLF2 and SLF1/2-the counterparts of yeast Nse5/6 (Oravcová, eLife, 2022). Notably, only SIMC1-SLF2 recruits SMC5/6 to SV40 Large T antigen (LT) foci in PML nuclear bodies (PML NBs), suggesting that these regulatory subcomplexes direct distinct roles of SMC5/6 on chromosomal versus ecDNA. However, their roles in plasmid repression remain unclear. Here, we demonstrate that SMC5/6-mediated repression of plasmid transcription depends exclusively on SIMC1-SLF2, whereas SLF1/2 is dispensable. Reinforcing its specialized role in ecDNA suppression, SIMC1-SLF2 does not participate in SMC5/6 recruitment to chromosomal DNA lesions. We further show that plasmid silencing requires a conserved interaction between SIMC1-SLF2 and SMC6, mirroring the functional relationship observed between yeast Nse5/6 and Smc6. As for viral silencing, plasmid repression depends on the SUMO pathway; however, unlike viral silencing, it does not require PML NBs. Additionally, we find that LT interacts with SMC5/6 and increases plasmid transcription to levels observed in SIMC1-SLF2-deficient cells-echoing the antagonistic roles of HBx (HBV) and Vpr (HIV-1) in viral genome repression. These findings expand the paradigm of viral antagonism against SMC5/6-mediated silencing, positioning LT as a novel player in this evolutionary tug-of-war.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
QuickProt: A bioinformatics and visualization tool for DIA and PRM mass spectrometry-based proteomics datasets. QuickProt:用于基于 DIA 和 PRM 质谱的蛋白质组学数据集的生物信息学和可视化工具。
bioRxiv : the preprint server for biology Pub Date : 2025-03-28 DOI: 10.1101/2025.03.24.645047
Omar Arias-Gaguancela, Carmen Palii, Mehar Un Nissa, Marjorie Brand, Jeff Ranish
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