{"title":"Unravelling the endoplasmic reticulum–Golgi intermediate compartment in plant cells","authors":"","doi":"10.1038/s41556-025-01629-6","DOIUrl":"https://doi.org/10.1038/s41556-025-01629-6","url":null,"abstract":"The existence of an endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC) in plant cells has long been debated. In our study we identified a dynamic Golgi-independent tubular network that transports ER-derived cargos and interacts with pre-existing Golgi to mature into new pre-Golgi cisternae in a lipid-dependent manner.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"1 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545836","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":"Sugar unmasking for trafficking","authors":"David A. Calderwood, Derek Toomre","doi":"10.1038/s41556-025-01615-y","DOIUrl":"https://doi.org/10.1038/s41556-025-01615-y","url":null,"abstract":"Cell surface acidification has key roles in both cell migration and bone resorption. A study now identifies a pathway whereby growth factor signalling induces local acidification, driving sialic acid removal and galectin-3-mediated integrin internalization.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"38 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538708","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":"ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion","authors":"Yuran Duan, Zhiqiang Hu, Peng Han, Bo Lei, Shuo Wang, Zheng Wang, Yueru Hou, Yanni Lin, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Shenghan Lou, Laishou Yang, Xueli Bai, Shengzhong Duan, Peng Zhan, Tong Liu, Zhimin Lu, Daqian Xu","doi":"10.1038/s41556-025-01627-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01627-8","url":null,"abstract":"<p>Highly aggressive tumours have evolved to restrain the cGAS–STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL–STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"9 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532308","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}
Yizeng Fan, Yuzhao Wang, Weichao Dan, Yilei Zhang, Li Nie, Zhiqiang Ma, Yanxin Zhuang, Bo Liu, Mengxing Li, Tianjie Liu, Zixi Wang, Leihong Ye, Yi Wei, Yuzeshi Lei, Chendong Guo, Jiale An, Chi Wang, Yulin Zhang, Jin Zeng, Wenyi Wei, Boyi Gan, Lei Li
{"title":"PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer","authors":"Yizeng Fan, Yuzhao Wang, Weichao Dan, Yilei Zhang, Li Nie, Zhiqiang Ma, Yanxin Zhuang, Bo Liu, Mengxing Li, Tianjie Liu, Zixi Wang, Leihong Ye, Yi Wei, Yuzeshi Lei, Chendong Guo, Jiale An, Chi Wang, Yulin Zhang, Jin Zeng, Wenyi Wei, Boyi Gan, Lei Li","doi":"10.1038/s41556-025-01610-3","DOIUrl":"https://doi.org/10.1038/s41556-025-01610-3","url":null,"abstract":"<p>The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into <i>S</i>-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"33 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532287","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}
Bicna Song, Dingyu Liu, Weiwei Dai, Natalie F. McMyn, Qingyang Wang, Dapeng Yang, Adam Krejci, Anatoly Vasilyev, Nicole Untermoser, Anke Loregger, Dongyuan Song, Breanna Williams, Bess Rosen, Xiaolong Cheng, Lumen Chao, Hanuman T. Kale, Hao Zhang, Yarui Diao, Tilmann Bürckstümmer, Janet D. Siliciano, Jingyi Jessica Li, Robert F. Siliciano, Danwei Huangfu, Wei Li
{"title":"Decoding heterogeneous single-cell perturbation responses","authors":"Bicna Song, Dingyu Liu, Weiwei Dai, Natalie F. McMyn, Qingyang Wang, Dapeng Yang, Adam Krejci, Anatoly Vasilyev, Nicole Untermoser, Anke Loregger, Dongyuan Song, Breanna Williams, Bess Rosen, Xiaolong Cheng, Lumen Chao, Hanuman T. Kale, Hao Zhang, Yarui Diao, Tilmann Bürckstümmer, Janet D. Siliciano, Jingyi Jessica Li, Robert F. Siliciano, Danwei Huangfu, Wei Li","doi":"10.1038/s41556-025-01626-9","DOIUrl":"https://doi.org/10.1038/s41556-025-01626-9","url":null,"abstract":"<p>Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies ‘buffered’ and ‘sensitive’ response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (<i>CCDC6</i>) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495326","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":"Systematic reconstruction of molecular pathway signatures using scalable single-cell perturbation screens","authors":"Longda Jiang, Carol Dalgarno, Efthymia Papalexi, Isabella Mascio, Hans-Hermann Wessels, Huiyoung Yun, Nika Iremadze, Gila Lithwick-Yanai, Doron Lipson, Rahul Satija","doi":"10.1038/s41556-025-01622-z","DOIUrl":"https://doi.org/10.1038/s41556-025-01622-z","url":null,"abstract":"<p>Recent advancements in functional genomics have provided an unprecedented ability to measure diverse molecular modalities, but predicting causal regulatory relationships from observational data remains challenging. Here, we leverage pooled genetic screens and single-cell sequencing (Perturb-seq) to systematically identify the targets of signalling regulators in diverse biological contexts. We demonstrate how Perturb-seq is compatible with recent and commercially available advances in combinatorial indexing and next-generation sequencing, and perform more than 1,500 perturbations split across six cell lines and five biological signalling contexts. We introduce an improved computational framework (Mixscale) to address cellular variation in perturbation efficiency, alongside optimized statistical methods to learn differentially expressed gene lists and conserved molecular signatures. Finally, we demonstrate how our Perturb-seq derived gene lists can be used to precisely infer changes in signalling pathway activation for in vivo and in situ samples. Our work enhances our understanding of signalling regulators and their targets, and lays a computational framework towards the data-driven inference of an ‘atlas’ of perturbation signatures.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"66 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495327","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}
Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes
{"title":"Publisher Correction: Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis","authors":"Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes","doi":"10.1038/s41556-025-01643-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01643-8","url":null,"abstract":"<p>Correction to: <i>Nature Cell Biology</i> https://doi.org/10.1038/s41556-025-01616-x, published online 21 February 2025.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"14 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495834","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":"ER-to-Golgi trafficking through a dynamic intermediate cis-Golgi tubular network in Arabidopsis","authors":"Louise Fougère, Magali Grison, Patricia Laquel, Matheus Montrazi, Fabrice Cordelières, Mónica Fernández-Monreal, Christel Poujol, Tomohiro Uemura, Akihiko Nakano, Yoko Ito, Yohann Boutté","doi":"10.1038/s41556-025-01624-x","DOIUrl":"https://doi.org/10.1038/s41556-025-01624-x","url":null,"abstract":"<p>Endoplasmic reticulum (ER)-to-Golgi trafficking is a central process of the secretory system of eukaryotic cells that ensures proper spatiotemporal sorting of proteins and lipids. However, the nature of the ER–Golgi intermediate compartments (ERGICs) and the molecular mechanisms mediating the transition between ERGICs and the Golgi, as well as the universality of these processes among eukaryotes, remain undiscovered. Here we identify a reticulated tubulo-vesicular network, labelled by MEMBRIN proteins, that is mostly independent of the Golgi, highly dynamic at the ER–Golgi interface and crossed by ER-induced released luminal cargos. We find that plant ERGICs become stabilized by the interaction they establish with pre-existing Golgi and gradually mature into Golgi cisternae, this process being dependent on C24-ceramide sphingolipids. Our study is a major twist in the understanding of the Golgi, as it identifies that the ERGICs in plants comprise a Golgi-independent and highly dynamic tubular network from which arise more stable Golgi-associated pre-cisternae structures.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"31 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485664","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 class of large cell-like extracellular vesicles","authors":"Crislyn D’Souza-Schorey, Dolores Di Vizio","doi":"10.1038/s41556-025-01611-2","DOIUrl":"https://doi.org/10.1038/s41556-025-01611-2","url":null,"abstract":"Recent discoveries in the field of large extracellular vesicles have revealed a greater diversity in subtypes than was appreciated even only a decade or so ago. A study now describes a cell-autonomous, motile, organelle-rich extracellular vesicle with cell-like functions and the largest one yet — the blebbisome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"17 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462171","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}
Dennis K. Jeppesen, Zachary C. Sanchez, Noah M. Kelley, James B. Hayes, Jessica Ambroise, Emma N. Koory, Evan Krystofiak, Nilay Taneja, Qin Zhang, Matthew M. Dungan, Olivia L. Perkins, Matthew J. Tyska, Ela W. Knapik, Kevin M. Dean, Amanda C. Doran, Robert J. Coffey, Dylan T. Burnette
{"title":"Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties","authors":"Dennis K. Jeppesen, Zachary C. Sanchez, Noah M. Kelley, James B. Hayes, Jessica Ambroise, Emma N. Koory, Evan Krystofiak, Nilay Taneja, Qin Zhang, Matthew M. Dungan, Olivia L. Perkins, Matthew J. Tyska, Ela W. Knapik, Kevin M. Dean, Amanda C. Doran, Robert J. Coffey, Dylan T. Burnette","doi":"10.1038/s41556-025-01621-0","DOIUrl":"https://doi.org/10.1038/s41556-025-01621-0","url":null,"abstract":"<p>Cells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"16 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462173","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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