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Kinesin light chain 1 (KLC1) interacts with NS1 and is a susceptibility factor for dengue virus infection in mosquito cells.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.20.644413
Juan Manuel Castillo, Raymundo Cruz Pérez, Daniel Talamás, Juan E Ludert
{"title":"Kinesin light chain 1 (KLC1) interacts with NS1 and is a susceptibility factor for dengue virus infection in mosquito cells.","authors":"Juan Manuel Castillo, Raymundo Cruz Pérez, Daniel Talamás, Juan E Ludert","doi":"10.1101/2025.03.20.644413","DOIUrl":"https://doi.org/10.1101/2025.03.20.644413","url":null,"abstract":"<p><p>A hallmark of the dengue virus (DENV) infection is the manipulation of host cell membranes, lipid trafficking and lipid droplets (LDs), all cellular functions that depend on the cytoskeleton and the cytoplasmatic streaming system. We previously reported the interaction between DENV NS1 protein and members of the kinesin motor complex in the <i>Aedes albopictus</i> cell line C6/36. In this work, we present evidence indicating that the protein kinesin light chain 1 (KLC1) is indeed a susceptibility factor for DENV replicative cycle in mosquito cells. The interaction between NS1 and KLC1 was confirmed by proximity ligation and co-immunoprecipitation assays in cells harvested 24 hpi. In addition, transmission immunoelectron microscopy showed KLC1 decorating the surface of vacuoles in association with NS1. Increased levels of KLC1 were observed starting at 6 hpi, suggesting that virus infection stimulates KLC1 synthesis. Silencing KLC1 expression results in a reduction in viral genome synthesis, decreased secretion of NS1, and a reduction of virus progeny by nearly 1 log. In agreement, similar affectations were observed in infected cells transfected with a peptide that competes and interferes with the interaction between KLC1 and its cargo molecules. Of note, both silencing the expression or interfering with the function of KLC1 resulted in a disorganization of LDs, which decreased in number and increased in area, in mock or infected cells. These results, taken together, suggest that KLC1 is a host susceptibility factor for DENV in mosquito cells, necessary for the proper transport and homeostasis of LDs required for flavivirus replication. However, modest colocalization was observed between NS1 and LDs, and the significance of the KLC1 and NS1 interactions need to be further investigated.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757284","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
3D printing cytoskeletal networks: ROS-induced filament severing leads to surge in actin polymerization.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.19.644260
Thomas Litschel, Dimitrios Vavylonis, David A Weitz
{"title":"3D printing cytoskeletal networks: ROS-induced filament severing leads to surge in actin polymerization.","authors":"Thomas Litschel, Dimitrios Vavylonis, David A Weitz","doi":"10.1101/2025.03.19.644260","DOIUrl":"https://doi.org/10.1101/2025.03.19.644260","url":null,"abstract":"<p><p>The cytoskeletal protein actin forms a spatially organized biopolymer network that plays a central role in many cellular processes. Actin filaments continuously assemble and disassemble, enabling cells to rapidly reorganize their cytoskeleton. Filament severing accelerates actin turnover, as both polymerization and depolymerization rates depend on the number of free filament ends - which severing increases. Here, we use light to control actin severing in vitro by locally generating reactive oxygen species (ROS) with photosensitive molecules such as fluorophores. We see that ROS sever actin filaments, which increases actin polymerization in our experiments. However, beyond a certain threshold, excessive severing leads to the disassembly of actin networks. Our experimental data is supported by simulations using a kinetic model of actin polymerization, which helps us understand the underlying dynamics. In cells, ROS are known to regulate the actin cytoskeleton, but the molecular mechanisms are poorly understood. Here we show that, in vitro, ROS directly affect actin reorganization.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757298","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
Resilience and vulnerabilities of tumor cells under purine shortage stress.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.19.644180
Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang
{"title":"Resilience and vulnerabilities of tumor cells under purine shortage stress.","authors":"Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang","doi":"10.1101/2025.03.19.644180","DOIUrl":"https://doi.org/10.1101/2025.03.19.644180","url":null,"abstract":"<p><p>Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757431","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
Two Axes of White Matter Development.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.19.644049
Audrey C Luo, Steven L Meisler, Valerie J Sydnor, Aaron Alexander-Bloch, Joëlle Bagautdinova, Deanna M Barch, Dani S Bassett, Christos Davatzikos, Alexandre R Franco, Jeff Goldsmith, Raquel E Gur, Ruben C Gur, Fengling Hu, Marc Jaskir, Gregory Kiar, Arielle S Keller, Bart Larsen, Allyson P Mackey, Michael P Milham, David R Roalf, Golia Shafiei, Russell T Shinohara, Leah H Somerville, Sarah M Weinstein, Jason D Yeatman, Matthew Cieslak, Ariel Rokem, Theodore D Satterthwaite
{"title":"Two Axes of White Matter Development.","authors":"Audrey C Luo, Steven L Meisler, Valerie J Sydnor, Aaron Alexander-Bloch, Joëlle Bagautdinova, Deanna M Barch, Dani S Bassett, Christos Davatzikos, Alexandre R Franco, Jeff Goldsmith, Raquel E Gur, Ruben C Gur, Fengling Hu, Marc Jaskir, Gregory Kiar, Arielle S Keller, Bart Larsen, Allyson P Mackey, Michael P Milham, David R Roalf, Golia Shafiei, Russell T Shinohara, Leah H Somerville, Sarah M Weinstein, Jason D Yeatman, Matthew Cieslak, Ariel Rokem, Theodore D Satterthwaite","doi":"10.1101/2025.03.19.644049","DOIUrl":"https://doi.org/10.1101/2025.03.19.644049","url":null,"abstract":"<p><p>Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total <i>N</i> = 2,710). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns with the cortical hierarchy defined by the sensorimotor-association axis, with tract ends adjacent to sensorimotor cortices maturing earlier than those adjacent to association cortices. These results reveal developmental variation along tracts that conventional tract-average analyses have previously obscured, challenging the implicit assumption that white matter tracts mature uniformly along their length. Such developmental variation along tracts may have functional implications, including mitigating ephaptic coupling in densely packed deep tract regions and tuning neural synchrony through hierarchical development in superficial tract regions - ultimately refining neural transmission in youth.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757620","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
Dietary L-3,4-dihydroxyphenylalanine (L-DOPA) augments cuticular melanization in Anopheles mosquitos while reducing their lifespan and malaria parasite burden.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2024.09.30.615839
Emma Camacho, Yuemei Dong, Christine Chrissian, Radames J B Cordero, Raúl G Saraiva, Yessenia Anglero-Rodriguez, Daniel F Q Smith, Ella Jacobs, Isabelle Hartshorn, Jose Alberto Patiño-Medina, Michael DePasquale, Amanda Dziedzic, Anne Jedlicka, Barbara Smith, Godfree Mlambo, Abhai Tripathi, Nichole A Broderick, Ruth E Stark, George Dimopoulos, Arturo Casadevall
{"title":"Dietary L-3,4-dihydroxyphenylalanine (L-DOPA) augments cuticular melanization in <i>Anopheles</i> mosquitos while reducing their lifespan and malaria parasite burden.","authors":"Emma Camacho, Yuemei Dong, Christine Chrissian, Radames J B Cordero, Raúl G Saraiva, Yessenia Anglero-Rodriguez, Daniel F Q Smith, Ella Jacobs, Isabelle Hartshorn, Jose Alberto Patiño-Medina, Michael DePasquale, Amanda Dziedzic, Anne Jedlicka, Barbara Smith, Godfree Mlambo, Abhai Tripathi, Nichole A Broderick, Ruth E Stark, George Dimopoulos, Arturo Casadevall","doi":"10.1101/2024.09.30.615839","DOIUrl":"https://doi.org/10.1101/2024.09.30.615839","url":null,"abstract":"<p><p>L-3,4-dihydroxyphenylalanine (L-DOPA), a naturally occurring tyrosine derivative, is prevalent in environments that include mosquito habitats, potentially serving as part of their diet. Given its role as a precursor for melanin synthesis we investigate the effect of dietary L-DOPA on mosquito physiology and immunity to <i>Plasmodium falciparum</i> and <i>Cryptococcus neoformans</i> infection. Dietary L-DOPA is incorporated into mosquito melanin via a non-canonical pathway and has a profound transcriptional effect associated with enhanced immunity, increased pigmentation, and reduced lifespan. Increased melanization results in an enhanced capacity to absorb electromagnetic radiation that affects mosquito temperatures. Bacteria in the mosquito microbiome act as sources of dopamine, a substrate for melanization. Our results illustrate how an environmentally abundant amino acid analogue can affect mosquito physiology and suggest its potential usefulness as an environmentally friendly vector control agent to reduce malaria transmission, warranting further research and field studies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756583","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 Critical Role for Neutral Sphingomyelinase-2 in Doxorubicin-induced Cardiotoxicity.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.20.644150
Samia Mohammed, Victoria Alvarado, Ya-Ping Jiang, Fabiola N Velazquez, Monica E Alexander, Folnetti A Alvarez, Danielle Lambadis, Sam B Chiappone, Anne G Ostermeyer-Fay, Leiqing Zhang, Achraf A Shamseddine, Daniel Canals, Ashley J Snider, Richard Z Lin, Yusuf A Hannun, Christopher J Clarke
{"title":"A Critical Role for Neutral Sphingomyelinase-2 in Doxorubicin-induced Cardiotoxicity.","authors":"Samia Mohammed, Victoria Alvarado, Ya-Ping Jiang, Fabiola N Velazquez, Monica E Alexander, Folnetti A Alvarez, Danielle Lambadis, Sam B Chiappone, Anne G Ostermeyer-Fay, Leiqing Zhang, Achraf A Shamseddine, Daniel Canals, Ashley J Snider, Richard Z Lin, Yusuf A Hannun, Christopher J Clarke","doi":"10.1101/2025.03.20.644150","DOIUrl":"https://doi.org/10.1101/2025.03.20.644150","url":null,"abstract":"<p><p>Although Doxorubicin (Dox) is an effective chemotherapeutic, its clinical utility is limited by a cumulative dose-dependent cardiotoxicity. While mechanisms underlying this cardiotoxicity have been investigated, strategies targeting these pathways have had marginal effects or had potential to interfere with Dox's anti-cancer activity. Sphingolipids (SL) are central to the chemotherapy response in multiple cancers, yet comparatively little is known about their role in non-transformed tissue, and actionable SL targets have not been identified. Here, we identified the SL enzyme neutral sphingomyelinase-2 (nSMase2) as a crucial downstream effector of Dox that is critical for chronic Dox-induced cardiotoxicity. <i>In vitro</i> studies showed that Dox treatment induces nSMase2 mRNA, protein, activity, and Cer accumulation in cardiomyocytes (CM) but not in cardiac fibroblasts. Mechanistically, nSMase2 induction was downstream of Top2B and p53, two previously identified molecular regulators of Dox-induced cardiotoxicity. <i>In vivo</i> studies in a chronic Dox model of cardiotoxicity found that loss of nSMase2 activity-null fro/fro mice were significantly protected from Dox-induced cardiac damage, exhibiting maintained ejection fraction, fractional shortening, and reduced left ventricle mass compared to wild-type littermates. Biologically, nSMase2 was dispensable for Dox-induced cell death but was important for Dox-induced CM senescence both <i>in vitro</i> and <i>in vivo</i> . Microarray analysis identified the dual specificity phosphatase DUSP4 as a downstream target of nSMase2 <i>in vitro</i> in Dox-treated CMs and <i>in vivo</i> in the chronic Dox-treated heart. Taken together, these results establish nSMase2 as a key component of the DNA damage response pathway in CMs and define a critical role for nSMase2 as a SL mediator of Dox-induced cardiotoxicity through effects on CM senescence. In addition to cementing a role for SLs in Dox effects in normal tissue, this study further advances nSMase2 as a target of interest for cardioprotection.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757199","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
Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.20.644383
Masihuz Zaman, Shu Yang, Ya Huang, Jay M Yarbro, Yanhong Hao, Zhen Wang, Danting Liu, Kiara E Harper, Hadeer Soliman, Alex Hemphill, Sarah Harvey, Shondra M Pruett-Miller, Valerie Stewart, Ajay Singh Tanwar, Ravi Kalathur, Christy R Grace, Martin Turk, Sagar Chittori, Yun Jiao, Zhiping Wu, Anthony A High, Xusheng Wang, Geidy E Serrano, Thomas G Beach, Gang Yu, Yang Yang, Ping-Chung Chen, Junmin Peng
{"title":"Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation.","authors":"Masihuz Zaman, Shu Yang, Ya Huang, Jay M Yarbro, Yanhong Hao, Zhen Wang, Danting Liu, Kiara E Harper, Hadeer Soliman, Alex Hemphill, Sarah Harvey, Shondra M Pruett-Miller, Valerie Stewart, Ajay Singh Tanwar, Ravi Kalathur, Christy R Grace, Martin Turk, Sagar Chittori, Yun Jiao, Zhiping Wu, Anthony A High, Xusheng Wang, Geidy E Serrano, Thomas G Beach, Gang Yu, Yang Yang, Ping-Chung Chen, Junmin Peng","doi":"10.1101/2025.03.20.644383","DOIUrl":"https://doi.org/10.1101/2025.03.20.644383","url":null,"abstract":"<p><p>Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with Aβ since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of <i>Mdk</i> gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimer's disease.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757434","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
SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.20.644437
Wenzhen Zhu, Linxiu Pan, Xianwei Cui, Anna Chiara Russo, Rohit Ray, Brent Pederson, Xiaoqiong Wei, Liangguang Leo Lin, Hannah Hafner, Brigid Gregg, Neha Shrestha, Chengyang Liu, Ali Naji, Peter Arvan, Darleen A Sandoval, Iris Lindberg, Ling Qi, Rachel B Reinert
{"title":"SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells.","authors":"Wenzhen Zhu, Linxiu Pan, Xianwei Cui, Anna Chiara Russo, Rohit Ray, Brent Pederson, Xiaoqiong Wei, Liangguang Leo Lin, Hannah Hafner, Brigid Gregg, Neha Shrestha, Chengyang Liu, Ali Naji, Peter Arvan, Darleen A Sandoval, Iris Lindberg, Ling Qi, Rachel B Reinert","doi":"10.1101/2025.03.20.644437","DOIUrl":"https://doi.org/10.1101/2025.03.20.644437","url":null,"abstract":"<p><p>Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet α cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observed a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we found that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein. These findings identify ERAD as a novel regulator of PC2 biology and an essential mechanism for maintaining α cell function.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757483","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
MYC Serine 62 phosphorylation promotes its binding to DNA double strand breaks to facilitate repair and cell survival under genotoxic stress.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.19.644227
Gabriel M Cohn, Colin J Daniel, Jennifer R Eng, Xiao-Xin Sun, Carl Pelz, Koei Chin, Alexander Smith, Charles D Lopez, Jonathan R Brody, Mu-Shui Dai, Rosalie C Sears
{"title":"MYC Serine 62 phosphorylation promotes its binding to DNA double strand breaks to facilitate repair and cell survival under genotoxic stress.","authors":"Gabriel M Cohn, Colin J Daniel, Jennifer R Eng, Xiao-Xin Sun, Carl Pelz, Koei Chin, Alexander Smith, Charles D Lopez, Jonathan R Brody, Mu-Shui Dai, Rosalie C Sears","doi":"10.1101/2025.03.19.644227","DOIUrl":"https://doi.org/10.1101/2025.03.19.644227","url":null,"abstract":"<p><p>Genomic instability is a hallmark of cancer, driving oncogenic mutations that enhance tumor aggressiveness and drug resistance. MYC, a master transcription factor that is deregulated in nearly all human tumors, paradoxically induces replication stress and associated DNA damage while also increasing expression of DNA repair factors and mediating resistance to DNA-damaging therapies. Emerging evidence supports a non-transcriptional role for MYC in preserving genomic integrity at sites of active transcription and protecting stalled replication forks under stress. Understanding how MYC's genotoxic and genoprotective functions diverge may reveal new therapeutic strategies for MYC-driven cancers. Here, we identify a non-canonical role of MYC in DNA damage response (DDR) through its direct association with DNA breaks. We show that phosphorylation at serine 62 (pS62-MYC) is crucial for the efficient recruitment of MYC to damage sites, its interaction with repair factors BRCA1 and RAD51, and effective DNA repair to support cell survival under stress. Mass spectrometry analysis with MYC-BioID2 during replication stress reveals a shift in MYC's interactome, maintaining DDR associations while losing transcriptional regulators. These findings establish pS62-MYC as a key regulator of genomic stability and a potential therapeutic target in cancers.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757525","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
Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.
bioRxiv : the preprint server for biology Pub Date : 2025-03-20 DOI: 10.1101/2025.03.19.643917
Ke Wang, Shayan Saniei, Nikita Poddar, Subrina Autar, Saul Carcamo, Meghana Sreenath, Jack H Peplinski, Rhonda E Ries, Isabella G Martinez, Clifford Chao, Anna Huo-Chang Mei, Noshin Rahman, Levan Mekerishvili, Miguel Quijada-Álamo, Grace Freed, Mimi Zhang, Katherine Lachman, Zayna Diaz, Manuel M Gonzalez, Jing Zhang, Giang Pham, Dan Filipescu, Mirela Berisa, Tommaso Balestra, Julie A Reisz, Angelo D'Alessandro, Daniel J Puleston, Emily Bernstein, Jerry E Chipuk, Mark Wunderlich, Sarah K Tasian, Bridget K Marcellino, Ian A Glass, Christopher M Sturgeon, Dan A Landau, Zhihong Chen, Eirini P Papapetrou, Franco Izzo, Soheil Meshinchi, Dan Hasson, Elvin Wagenblast
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