Cell DiscoveryPub Date : 2026-07-14DOI: 10.1038/s41421-026-00914-4
Arup R Nath, Sanskar Ranglani, Mohd Yaseen Malik, Jacek Szymanski, Anis Uz Zaman, Emmanouela Repapi, Roy Drissen, Natalie M Doig, Peter J Magill, Claus Nerlov, Liliana Minichiello
{"title":"Identification of a novel deeply quiescent neural stem cell population in the subventricular zone: a potential source for brain repair.","authors":"Arup R Nath, Sanskar Ranglani, Mohd Yaseen Malik, Jacek Szymanski, Anis Uz Zaman, Emmanouela Repapi, Roy Drissen, Natalie M Doig, Peter J Magill, Claus Nerlov, Liliana Minichiello","doi":"10.1038/s41421-026-00914-4","DOIUrl":"10.1038/s41421-026-00914-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structures of the Crimean-Congo hemorrhagic fever virus RNA-dependent RNA polymerase.","authors":"Mengyun Li, Kaixiang Zhu, Yanan Liu, Kun Shang, Yuanhao Li, Xinyue Wang, Jianing Wang, Jie Jia, Xin Ai, Dongcun Ni, Sheng Cui, Hongtao Zhu, Xiaopan Gao","doi":"10.1038/s41421-026-00905-5","DOIUrl":"10.1038/s41421-026-00905-5","url":null,"abstract":"<p><p>Crimean-Congo hemorrhagic fever virus (CCHFV), designated by the WHO as a priority pathogen under its R&D Blueprint for emerging epidemics, poses a major global health threat, yet licensed vaccines or specific antiviral treatments are lacking. As the sole viral enzyme responsible for genome replication and transcription, the CCHFV L protein is a large, multienzymatic protein, but its exceptional size (> 450 kDa) and extensive domain architecture have hindered structural analysis. Here, we present high-resolution cryo-electron microscopy structures of the full-length CCHFV L protein in its apo state and bound to the 5' viral RNA promoter. These structures reveal the largest polymerase known among Bunyavirales and demonstrate that the apo form adopts a highly flexible conformation in which multiple functional elements remain disordered. Binding of the 5' promoter RNA triggers extensive conformational rearrangements that organize these elements into a catalytically competent active site. We define a conserved 5' hook-binding mode and identify two previously unrecognized residues (K1545 and E1637) that form a constriction at the NTP entry channel, representing newly defined regulatory motifs J and K conserved across Bunyavirales. We further characterize an expanded pendant domain unique to nairoviruses that, although not essential for promoter binding, likely modulates template movement within the internal tunnel during RNA synthesis. Our results provide the first structural framework for a nairovirus polymerase, illuminate the mechanisms of CCHFV RNA synthesis, and establish a foundation for structure-guided antiviral development against this high-priority pathogen.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Sympathetic nervous system-mediated fibro-adipogenic progenitor mobilization drives stroke-related sarcopenia.","authors":"Yinong Huang, Yilin Liu, Ruijie Li, Mingming Fan, Yixuan Liu, Yiling Wang, Xin Sui, Xiaofeng Yuan, Qiying Lu, Yuan Qiu, Ruijun Li, Jierui Chen, Bingjun Zhang, Sanxin Liu, Chuyun Ou, Yuanchen Ma, Xiaofan Lai, Jie Ren, Zhengqi Lu, Huimin Yi, Weijun Huang, Jiancheng Wang, Yanbing Li, Haipeng Xiao, Andy Peng Xiang","doi":"10.1038/s41421-026-00899-0","DOIUrl":"10.1038/s41421-026-00899-0","url":null,"abstract":"<p><p>Patients who survive stroke usually experience rapid muscle wasting and an increased risk of physical disability. Although multifactorial interactions, including malnutrition, disuse, systemic catabolic imbalance, and neurohormonal dysregulation, are thought to contribute to the progression of stroke-related sarcopenia, the underlying mechanisms of this brain-muscle crosstalk remain elusive. Muscle-resident fibro-adipogenic progenitors (FAPs) are indispensable for maintaining muscle homeostasis and function as initial sensors of external perturbations. In the present study, we report that FAPs rapidly respond to the overactive sympathetic nervous system (SNS) and egress from the muscle niche into circulation during the acute phase of stroke. FAP-specific ablation of adrenoceptor beta 2 (Adrb2) markedly ameliorated stroke-related sarcopenia, highlighting the central role of SNS-mediated FAP loss in its pathogenesis. Mechanistically, increased norepinephrine release initiates FAP mobilization through the activation of pro-migratory signals and the degradation of extracellular matrix components. Using transcriptomic profiling, we further characterized insulin growth factor-1 (IGF-1) as a key anti-atrophic executive factor predominantly derived from FAPs. Collectively, our work demonstrates that the SNS-mediated loss of FAPs and subsequent compromised IGF-1 secretion contribute to sarcopenia in mice following stroke. Targeting this mechanism by early anti-sympathetic treatment with propranolol may effectively restore muscle homeostasis and mass after stroke.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell DiscoveryPub Date : 2026-07-07DOI: 10.1038/s41421-026-00902-8
Thierry Cheutin, Nazli Akilli, Marco Di Stefano, Paul-Swann Puel, Lauriane Fritsch, Daniel Jost, Giacomo Cavalli
{"title":"PRC1 nanoglobules organize Hox chromatin during Drosophila embryogenesis.","authors":"Thierry Cheutin, Nazli Akilli, Marco Di Stefano, Paul-Swann Puel, Lauriane Fritsch, Daniel Jost, Giacomo Cavalli","doi":"10.1038/s41421-026-00902-8","DOIUrl":"10.1038/s41421-026-00902-8","url":null,"abstract":"<p><p>Polycomb group (PcG) proteins are required to maintain the silencing of key developmental genes during development. In Drosophila, they bind to discrete genomic elements named Polycomb response elements (PREs). PcG proteins form two classes of complexes. Polycomb repressive complex 2 (PRC2) deposits H3K27me3, a histone mark that covers large chromatin domains. The canonical PRC1 complex can bind to PREs as well as to the H3K27me3 mark. Inside the cell nucleus, when analyzed by confocal microscopy, the PcG subunits and associated chromatin are localized to polycomb foci. However, the lack of spatial resolution of this method impedes the precise localization of the polycomb machinery relative to its target chromatin. To resolve this long-standing problem, we analyzed Drosophila embryos by superresolution stimulated emission depletion microscopy. We observed that polycomb foci associated with Hox gene clusters are composed of multiple dynamic PRC1 substructures, which we named \"PRC1 nanoglobules\". PREs are more associated with these nanoglobules than the surrounding H3K27me3 chromatin. By imaging the entire Bithorax complex (BX-C) locus, we identified chromatin substructures that partially overlap with PRC1 nanoglobules, indicating that they form different assemblies. Furthermore, polymer simulations suggest that interactions between PREs and PRC1 nanoglobules can drive the compaction and positioning of the BX-C domain. Taken together, these data suggest that by establishing the three-dimensional architecture of their target loci, PRC1 nanoglobules are key molecular assemblies that maintain polycomb-dependent silencing.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13338358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Longitudinal single-cell and TCR repertoire profiling characterizes clonal entrapment in patients with pMMR/MSS locally advanced rectal cancer.","authors":"Zhichun Tang, Mingxuan Zhu, Shidong Zhao, Dazhi Pang, Yancheng Cui, Guole Lin, Aiwen Wu, Yilin Lin, Xinyang Jiang, Wei Zhang, Nan Xiong, Changjiang Yang, Caihong Wang, Shan Wang, Yingjiang Ye, Fan Bai, Zhanlong Shen","doi":"10.1038/s41421-026-00900-w","DOIUrl":"10.1038/s41421-026-00900-w","url":null,"abstract":"<p><p>Elevated intratumoral immune inflammation prior to treatment is typically associated with better outcomes in hot tumors treated with immune checkpoint inhibitors (ICIs). However, we observed a paradox in pMMR/MSS locally advanced rectal cancer (LARC) patients, where a subset with elevated baseline immune inflammation exhibited worse outcomes after combined radiotherapy and ICI treatment compared with patients with minimal immune inflammation. To investigate this counterintuitive finding, we performed paired scRNA-seq and scTCR-seq on longitudinally collected samples, including tumor biopsies (pre-treatment, post-radiotherapy, and post-immunotherapy) and peripheral blood mononuclear cells (pre-treatment and post-immunotherapy), from 20 pMMR/MSS LARC patients treated with sequential radiotherapy and ICI therapy (NCT06493240). We propose the concept of clonal entrapment to explain this phenomenon. Specifically, our profiling results reveal that increased HLA-DQA2 expression in dendritic cells and upregulated GDF15 expression in treatment-resistant tumor cells correlate with the restricted expansion of novel tumor-reactive TCR clonotypes. Consequently, the immune response is limited primarily by pre-existing TCR clonotypes within the tumor, especially those partially expanded under chronic inflammation, leading to the expansion of TCR clonotypes derived mainly from pre-treatment CD8<sup>+</sup> T cell pools following ICI therapy. By identifying this feature of the pMMR/MSS LARC microenvironment, our study provides a high-resolution framework for understanding resistance to sequential radiotherapy and ICI therapy.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RNA helicase DDX6 governs ASC speck formation in P-bodies and the transition to stress granules via phase separation during inflammasome activation.","authors":"Rudi Mao, Yingqiao Liu, Zhenyu Fan, Yanfeng Li, Luyu Yang, Qingqing Xie, Hong-Peng Dong, Mingjun Bi, Chengjiang Gao, Zhe Yang, Tao Xu, Xiaopeng Qi","doi":"10.1038/s41421-026-00898-1","DOIUrl":"10.1038/s41421-026-00898-1","url":null,"abstract":"<p><p>The recruitment and condensation of apoptosis-associated speck-like protein containing a CARD (ASC) are critical for ASC speck formation and inflammasome activation. However, how this process occurs efficiently in vivo remains unclear. Here, we identified the RNA helicase DDX6 as an ASC-interacting protein through immunoprecipitation‒mass spectrometry (IP‒MS) analysis. DDX6 promotes the activation of both NLRP3 and AIM2 inflammasomes by facilitating the recruitment of ASC to these receptors through its RNA helicase activity. Mechanistically, DDX6 functions as a scaffold protein for processing body (P-body) assembly and drives ASC speck formation in P-bodies via liquid‒liquid phase separation (LLPS). We report that membrane integrity is associated with stress granule (SG) formation and that in Caspase-1<sup>-/-</sup>, Gsdmd<sup>-/-</sup>, or NINJ1-inhibited cells, DDX6 mediates initial ASC speck assembly in P-bodies, followed by their transition to SGs during inflammasome activation. DDX6 deficiency in macrophages increases host susceptibility to Listeria infection. Our results establish that DDX6 orchestrates ASC recruitment, speck formation, and subsequent transition through LLPS-mediated mechanisms, offering new insights into inflammasome assembly and potential therapeutic approaches for inflammasome-related diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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