{"title":"Nuclear N-glycosylation maintains H3K9me3 heterochromatin and genomic stability.","authors":"Xiuxiao Tang,Ranran Dai,Li Qing,Zhida Zhang,Hongmei Li,Lizi Lu,Hancheng Lin,Danling Ji,Wei Dan,Yuqi He,Xinyi Liu,Tao Yang,Wakam Chang,Yang Mao,Shisheng Sun,Junjun Ding","doi":"10.1038/s41556-026-01941-9","DOIUrl":"https://doi.org/10.1038/s41556-026-01941-9","url":null,"abstract":"Polysaccharides are known to be synthesized by enzymes in the endoplasmic reticulum and Golgi apparatus and transported through the secretory pathway to the cell surface or extracellular space, where they mediate essential biological processes. While classical localization and functions of polysaccharides are well established, their presence and potential roles in the nucleus remain unclear. Here we demonstrate that N-glycans, a type of polysaccharides, modify inner nuclear membrane (INM) proteins and are present in the cell nucleus across diverse cell types-a modification referred to as N-linked glycosylation (N-glycosylation). N-glycosylation is enriched in chromatin regions marked by H3K9me3 and long interspersed nuclear element-1 (LINE-1) retrotransposons. N-glycosylation inhibition and INM protein N-glycosylation site mutation both downregulate H3K9me3 within lamina-associated domains and lead to genomic instability. Mechanistically, N-glycosylation regulates the interaction between the histone H3K9 methyltransferase SETDB1 and INM proteins, promotes the association of SETDB1 with the INM, and maintains H3K9me3. Moreover, we reveal that canonical N-glycan biosynthetic machinery in the endoplasmic reticulum contributes to the N-glycosylation of INM proteins. These findings uncover a previously unrecognized nuclear role for polysaccharides, broadening our understanding beyond their traditional subcellular distributions and functional profiles.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bishal Tandukar, Delahny Deivendran, Limin Chen, Neda Bahrani, Defne Baskurt, Beatrice Weier, Harsh Sharma, Noel Cruz-Pacheco, Min Hu, Kayla Marks, Rebecca G. Zitnay, Aravind K. Bandari, Barbara Rentroia-Pacheco, Rojina Nekoonam, Boris C. Bastian, Iwei Yeh, Robert Judson-Torres, A. Hunter Shain
{"title":"Somatic mutations distinguish melanocyte subpopulations in human skin","authors":"Bishal Tandukar, Delahny Deivendran, Limin Chen, Neda Bahrani, Defne Baskurt, Beatrice Weier, Harsh Sharma, Noel Cruz-Pacheco, Min Hu, Kayla Marks, Rebecca G. Zitnay, Aravind K. Bandari, Barbara Rentroia-Pacheco, Rojina Nekoonam, Boris C. Bastian, Iwei Yeh, Robert Judson-Torres, A. Hunter Shain","doi":"10.1038/s41556-026-01943-7","DOIUrl":"https://doi.org/10.1038/s41556-026-01943-7","url":null,"abstract":"Here, to understand the homeostatic mechanisms governing melanocytes, we interrogate the mutational landscapes, gene-expression profiles and morphological features of 297 clonal expansions of epidermal melanocytes from 31 donors. We show that a population of melanocytes with low mutation burden persists in sun-exposed epidermis. These cells are smaller, less dendritic, and exhibit stem-like expression profiles when compared to melanocytes carrying high mutation burdens. Using single-cell spatial transcriptomics, we show that melanocytes inferred to have low mutation burdens localize to both hair follicles and interfollicular epidermis, whereas melanocytes with high mutation burdens are largely restricted to epidermis. We propose that melanocytes in the hair follicle occupy a privileged niche, protected from ultraviolet radiation, but replenish the epidermis following photodamage. This study highlights the value of incorporating mutational information into cell atlases. Cells can change their positions over time, but mutations provide a historical record of processes that were operative on each cell.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"32 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nina Kozlova, Kayla A. Cruz, Antoine A. Ruzette, Hanna M. Doh, Nicholas A. Willis, Su Min Hong, Raul S. Gonzalez, Monika Vyas, Laura M. Selfors, Stephan Dreyer, Rosie Upstill-Goddard, Kerrie L. Faia, Steve Wenglowsky, Josh Close, Alica Beutel, Zeljka Jutric, Michael U. J. Oliphant, Larysa Poluben, Byanjana Thapa, Martin S. Taylor, Venla Mustonen, Pradeep Mangalath, Christopher J. Halbrook, Joseph E. Grossman, Rosa F. Hwang, John G. Clohessy, Salla Ruskamo, Petri Kursula, Boryana Petrova, Naama Kanarek, Philip A. Cole, David K. Chang, Conor L. Evans, Simon F. Nørrelykke, Ralph Scully, Taru Muranen
{"title":"Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing","authors":"Nina Kozlova, Kayla A. Cruz, Antoine A. Ruzette, Hanna M. Doh, Nicholas A. Willis, Su Min Hong, Raul S. Gonzalez, Monika Vyas, Laura M. Selfors, Stephan Dreyer, Rosie Upstill-Goddard, Kerrie L. Faia, Steve Wenglowsky, Josh Close, Alica Beutel, Zeljka Jutric, Michael U. J. Oliphant, Larysa Poluben, Byanjana Thapa, Martin S. Taylor, Venla Mustonen, Pradeep Mangalath, Christopher J. Halbrook, Joseph E. Grossman, Rosa F. Hwang, John G. Clohessy, Salla Ruskamo, Petri Kursula, Boryana Petrova, Naama Kanarek, Philip A. Cole, David K. Chang, Conor L. Evans, Simon F. Nørrelykke, Ralph Scully, Taru Muranen","doi":"10.1038/s41556-026-01938-4","DOIUrl":"https://doi.org/10.1038/s41556-026-01938-4","url":null,"abstract":"Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumours. They are unresponsive to treatments, and patients relapse quickly on DNA-damaging chemotherapies. PDAC stroma consists of extracellular matrix proteins (ECM), secreted by cancer-associated fibroblasts (CAFs). Here we show an unexpected link between CAF-secreted ECM proteins and enhanced DNA repair. We identify NDRG1 (N-myc downstream-regulated gene 1) as a key mediator that senses signals from the ECM via adhesion receptors and serum and glucocorticoid-activated kinase. We establish NDRG1 as a DNA repair factor that physically associates with replication forks, maintains DNA replication, resolves stalled forks caused by chemotherapies and is involved in reducing R-loops, RNA–DNA hybrids known to cause genomic instability. NDRG1 is highly expressed in PDAC tumours and its high expression correlates with poor disease-specific survival and poor response to chemotherapy. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in promoting DNA repair via NDRG1, mechanistically linking tumour stroma to replication fork homeostasis and R-loop regulation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"69 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariantonietta D'Ambrosio,Matthew E H White,Efthymios S Gavriil,Laura Bousset,Jodie Birch,Aleksandra Gruevska,Emiliano Pasquini,Manuel Colucci,Winnie Fong,Simone Mosole,Aurora Valdata,Dimitris Veroutis,Katie Tyson,Vikas Ranvir,Sandra Prokosch,Joaquim Pombo,Aoki Ardisson,Sanjay Khadayate,George Young,Alex Montoya,Georgia Roumelioti,Jack Houghton,Jianan Lu,Pavel V Shliaha,Elena De Vita,Santiago Vernia,Vassilis G Gorgoulis,Suchira Gallage,Mathias Heikenwälder,Zoe Hall,Andrea Alimonti,Iain A McNeish,Edward W Tate,Jesús Gil
{"title":"Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.","authors":"Mariantonietta D'Ambrosio,Matthew E H White,Efthymios S Gavriil,Laura Bousset,Jodie Birch,Aleksandra Gruevska,Emiliano Pasquini,Manuel Colucci,Winnie Fong,Simone Mosole,Aurora Valdata,Dimitris Veroutis,Katie Tyson,Vikas Ranvir,Sandra Prokosch,Joaquim Pombo,Aoki Ardisson,Sanjay Khadayate,George Young,Alex Montoya,Georgia Roumelioti,Jack Houghton,Jianan Lu,Pavel V Shliaha,Elena De Vita,Santiago Vernia,Vassilis G Gorgoulis,Suchira Gallage,Mathias Heikenwälder,Zoe Hall,Andrea Alimonti,Iain A McNeish,Edward W Tate,Jesús Gil","doi":"10.1038/s41556-026-01921-z","DOIUrl":"https://doi.org/10.1038/s41556-026-01921-z","url":null,"abstract":"Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"100 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Riddhiman K. Garge, Valerie Lynch, Rose Fields, Silvia Casadei, Sabrina Best, Jeremy Stone, Matthew Snyder, Connor Kubo, Arata Wakimoto, Zukai Liu, Chris D. McGann, Jay Shendure, Lea M. Starita, Nobuhiko Hamazaki, Devin K. Schweppe
{"title":"The proteomic landscape and temporal dynamics of human and mouse gastruloid development","authors":"Riddhiman K. Garge, Valerie Lynch, Rose Fields, Silvia Casadei, Sabrina Best, Jeremy Stone, Matthew Snyder, Connor Kubo, Arata Wakimoto, Zukai Liu, Chris D. McGann, Jay Shendure, Lea M. Starita, Nobuhiko Hamazaki, Devin K. Schweppe","doi":"10.1038/s41556-026-01937-5","DOIUrl":"https://doi.org/10.1038/s41556-026-01937-5","url":null,"abstract":"The embryo establishes a body plan and primes itself for organogenesis during gastrulation. As gastrulation is challenging to study in vivo, stem-cell-derived ‘gastruloids’ have emerged as powerful surrogates. Although transcriptomics and imaging have been applied extensively to such embryo models, the dynamics of their proteomes remains largely unknown. Here we apply quantitative proteomics to human and mouse gastruloids at four key stages. We leverage these data to map the expression dynamics of protein complexes, and to nominate cooperative proteins. With matched transcriptome data, we investigate global and stage-specific discordance between the transcriptome and proteome and leverage phosphosite dynamics to nominate kinase–substrate relationships. Finally, we apply co-regulation network analysis to identify genes linked to the Commander complex, the perturbation of which leads to morphological defects in gastruloids. Altogether, our work showcases the potential of applying proteomics to embryo models to advance our understanding of mammalian development in ways challenging through transcriptomics alone.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chen Wang,Yi Pan,Ruochen Dong,Wenxuan Zhou,Xiaduo Meng,Xi Kang,Ravi Nistala,Richard D Hammer,Linheng Li,XunLei Kang
{"title":"Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour.","authors":"Chen Wang,Yi Pan,Ruochen Dong,Wenxuan Zhou,Xiaduo Meng,Xi Kang,Ravi Nistala,Richard D Hammer,Linheng Li,XunLei Kang","doi":"10.1038/s41556-026-01939-3","DOIUrl":"https://doi.org/10.1038/s41556-026-01939-3","url":null,"abstract":"Leukaemic stem cells (LSCs) reside in protective bone marrow (BM) niches that promote therapeutic resistance and relapse. Here we characterized longitudinal BM niches supporting LSC survival, distinguishing the metaphysis from the central marrow. Quiescent LSCs preferentially localized to the metaphysis and exhibited reduced stemness and aggressiveness upon mobilization to the central marrow. Targeting DPP4 in acute myeloid leukaemia (AML) cells altered CXCL12 gradients at three spatial scales. Systemically, reversal of the BM-peripheral blood CXCL12 gradient confined AML cells within the BM. At the BM level, disruption of the metaphysis-central marrow gradient displaced LSCs from their protective niche. At the microscale, loss of the CXCL12 gradient between N-cadherin+ stromal cells and the surrounding matrix impaired LSC recruitment. These effects arise from the CXCL12-DPP4-GPC3 axis, in which DPP4 truncates and inactivates CXCL12, whereas stromal GPC3 restrains DPP4 activity. Modulating this axis disrupts niche protection and enhances therapeutic vulnerability in AML.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"68 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147738986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A lipid-centric view of endocytosis by caveolae.","authors":"Robert G Parton,Michael M Kozlov,Richard Lundmark","doi":"10.1038/s41556-026-01945-5","DOIUrl":"https://doi.org/10.1038/s41556-026-01945-5","url":null,"abstract":"Caveolae have long been considered to be an alternative endocytic pathway, with distinct cargoes, but generally similar functions, to clathrin-coated pits. Here we suggest that the mechanisms of caveola formation and their scission are tightly interlinked and rely on specific lipids. These mechanisms are fundamentally different to those driving the formation and fission of coated pits. Both formation and scission of caveolae are driven by lipid-induced shaping of the caveolar domain, and we present biophysical models for lipid-driven curvature generation and its coupling with scission. In addition, we propose that these new insights have important implications for understanding the function of endocytosis mediated by caveolae. Rather than a parallel endocytic pathway for protein cargo, we argue that caveolae are a lipid-sensitive mobilized multifunctional surface domain.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"5 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147735345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shiyu Sun, Yi Zheng, Yung Su Kim, Zheng Zhong, Norio Kobayashi, Xufeng Xue, Yue Liu, Zhuowei Zhou, Yanhong Xu, Jinglei Zhai, Hongmei Wang, Jianping Fu
{"title":"A transgene-free, human peri-gastrulation embryo model presents trilaminar embryonic disc-, amnion- and yolk sac-like structures","authors":"Shiyu Sun, Yi Zheng, Yung Su Kim, Zheng Zhong, Norio Kobayashi, Xufeng Xue, Yue Liu, Zhuowei Zhou, Yanhong Xu, Jinglei Zhai, Hongmei Wang, Jianping Fu","doi":"10.1038/s41556-026-01930-y","DOIUrl":"https://doi.org/10.1038/s41556-026-01930-y","url":null,"abstract":"Human peri-gastrulation is a critical developmental stage, yet challenging to study directly. Stem cell-based embryo models have emerged as promising tools for probing early human embryogenesis. Here we report a transgene-free human embryo model, namely peri-gastrulation trilaminar embryonic disc (PTED) embryoid, derived exclusively from primed human pluripotent stem cells, recapitulating certain features of peri-gastrulation human development, which include the formation of trilaminar embryonic layers positioned between the dorsal amnion and ventral definitive yolk sac, as well as primitive haematopoiesis. Our lineage tracing showed that, in PTED embryoids, embryonic and extraembryonic mesoderm as well as embryonic and extraembryonic endoderm arise from gastrulating epiblast-like cells, which provides support for extraembryonic lineage potential of peri-gastrulation human epiblast. Notably, active haematopoiesis and blood-cell generation occurred within the definitive yolk sac-like structure of PTED embryoids. Together, PTED embryoids offer a tractable and ethically less complex model for investigating the self-organizing properties of human peri-gastrulation development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"5 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Organellar insights in ageing and longevity.","authors":"Philip Mannino,Mooncheol Park,Meng Carla Wang","doi":"10.1038/s41556-026-01927-7","DOIUrl":"https://doi.org/10.1038/s41556-026-01927-7","url":null,"abstract":"Metabolic processes shape ageing and longevity at multiple levels. Emerging evidence shows that many of these processes are orchestrated within and between cellular organelles. Organelles function not only as metabolic reactors but also as signalling hubs, and their coordination plays crucial roles in maintaining cellular homeostasis and promoting organismal fitness. Rather than acting in isolation, organelles engage in dynamic crosstalk through membrane contact sites, metabolite exchange and signalling interplay. In recent years, organelles have been increasingly recognized as critical regulators of ageing and longevity. Here we summarize age-related organellar changes, highlight organelle-mediated intra- and intercellular signalling communication in lifespan and healthspan regulation, and discuss the active roles of organelles in microbiome-host interactions and transgenerational inheritance in regulating longevity. We further outline how longevity-promoting interventions influence organelles, and provide perspectives on how future technological advances may further accelerate progress in this emerging research topic.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"17 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shanshan Liu (刘珊珊), Mark Gad, Caifan Li (李采蘩), Kevin Cho, Yuyang Liu (刘雨洋), Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J. Patti, Ekaterina V. Vinogradova, Richard K. Hite, Kıvanç Birsoy
{"title":"SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis","authors":"Shanshan Liu \u0000 (刘珊珊), Mark Gad, Caifan Li \u0000 (李采蘩), Kevin Cho, Yuyang Liu \u0000 (刘雨洋), Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J. Patti, Ekaterina V. Vinogradova, Richard K. Hite, Kıvanç Birsoy","doi":"10.1038/s41556-026-01922-y","DOIUrl":"https://doi.org/10.1038/s41556-026-01922-y","url":null,"abstract":"The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"23 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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