Cell ResearchPub Date : 2025-08-20DOI: 10.1038/s41422-025-01173-w
Lin Liu, John Silke
{"title":"SIX of one and half-a-dozen USP2 regulating inflammation","authors":"Lin Liu, John Silke","doi":"10.1038/s41422-025-01173-w","DOIUrl":"10.1038/s41422-025-01173-w","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"701-702"},"PeriodicalIF":25.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01173-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944881","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 ResearchPub Date : 2025-08-18DOI: 10.1038/s41422-025-01164-x
Kui Xu, Guoying Hua, Mingdi Wu, Haihang Zhang, Jingda Liu, Hu Feng, Erwei Zuo
{"title":"AlphaCD: a machine learning model capable of highly accurate characterization for 21,335 cytidine deaminases","authors":"Kui Xu, Guoying Hua, Mingdi Wu, Haihang Zhang, Jingda Liu, Hu Feng, Erwei Zuo","doi":"10.1038/s41422-025-01164-x","DOIUrl":"10.1038/s41422-025-01164-x","url":null,"abstract":"The vast scope but limited-supporting evidence in sequence databases hinders identification of proteins with specific functionality. Here, we experimentally characterized catalytic efficiency, target site window, motif preference, and off-target activity of 1100 apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-like family cytidine deaminases (CDs) fused with nCas9 in HEK293T cells, thereby generating the largest dataset of experimentally validated functions for a single protein family to date. These data, together with amino acid sequence, three-dimensional structure, and eight additional features, were used to construct a machine learning (ML) model, AlphaCD, which showed high accuracy in predicting catalytic efficiency (0.92) and off-target activity (0.84), as well as target windows (0.73) and catalytic motifs (0.78). We applied the trained model to predict the above catalytic features of 21,335 CDs in Uniprot, and subsampling of 28 CDs further validated its prediction accuracy (0.84, 0.87, 0.75, 0.73, respectively). Alanine scanning-based mutagenesis was then employed to reduce off-targets in one example CD, which produced a remarkably high fidelity, high efficiency cytosine base editor, thus demonstrating AlphaCD application in high-accuracy, high-throughput protein functional characterization, and providing a strategy for accelerated characterization of other proteins.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"750-761"},"PeriodicalIF":25.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871708","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}
Cell ResearchPub Date : 2025-08-18DOI: 10.1038/s41422-025-01163-y
Brianna Jarboe, Maria Shubina, Ryan A. Langlois, David F. Boyd, Siddharth Balachandran
{"title":"Lung cell fates during influenza","authors":"Brianna Jarboe, Maria Shubina, Ryan A. Langlois, David F. Boyd, Siddharth Balachandran","doi":"10.1038/s41422-025-01163-y","DOIUrl":"10.1038/s41422-025-01163-y","url":null,"abstract":"Roughly 1 billion people are infected by Influenza A viruses (IAVs) worldwide each year, resulting in approximately half a million deaths. Particularly concerning is the threat of IAV spillover from avian and other animal reservoirs. The recent outbreak of highly pathogenic avian influenza H5N1 in US dairy cows highlights this concern. While viruses that enter human populations from such zoonotic transmission typically lack the ability to transmit effectively between humans, they may be only a few mutations from acquiring this capacity. These newly adapted viruses have the potential to be significantly more virulent than seasonal strains. A major contributor to influenza pathology is the over-exuberant immune response to the virus, particularly when the infection is present in distal pulmonary tissues. Maladaptive immune pathway over-activation can drive tissue damage and pathology, often independently of effective viral control. Anti-inflammatories targeting host-initiated pathological processes hold promise, but these avenues require a thorough understanding of virus-triggered lung inflammation before they can be fully exploited. In this review, we will discuss recent advances in our understanding of the cell types that are targeted by IAV, the consequences of IAV infection on the biology of these cells, and their contribution to lung pathology in influenza. We will also discuss how virus-induced hyper-inflammatory responses present new entry-points for therapeutic intervention, showcasing Z-form nucleic acid-binding protein 1 (ZBP1)-initiated necroptosis as an example of one such pathway.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"707-718"},"PeriodicalIF":25.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01163-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871709","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 ResearchPub Date : 2025-08-15DOI: 10.1038/s41422-025-01165-w
Xi Lin, Xiaohu Wei, Ning Pu, Ling Wang, Zhibin Zhang, Cuixia Li, Yang Yue, Junlin Liu, Qiwen Tan, Qianqian Sun, Fei Xu
{"title":"Constitutive arrestin recruitment by orphan GPR52 via an atypical binding mode","authors":"Xi Lin, Xiaohu Wei, Ning Pu, Ling Wang, Zhibin Zhang, Cuixia Li, Yang Yue, Junlin Liu, Qiwen Tan, Qianqian Sun, Fei Xu","doi":"10.1038/s41422-025-01165-w","DOIUrl":"https://doi.org/10.1038/s41422-025-01165-w","url":null,"abstract":"<p>Dear Editor,</p><p>Arrestins and G proteins are integral to G protein-coupled receptor (GPCR) signal transduction, typically recruited following receptor activation by a ligand. Understanding the modes of interactions for arrestins provides insights into the complexity and versatility of cellular responses mediated by GPCRs. To date, only a few structures of agonist-activated GPCR–β-arrestin1 (βarr1) complexes have been resolved by cryo-electron microscopy (cryo-EM).<sup>1,2</sup> Interestingly, most of the reported GPCR–βarr1 complexes primarily exhibit core engagement conformations for βarr1, although an unstable ‘hanging’ conformation has also been observed for M2R–βarr1.<sup>3</sup> In contrast, the class B GCGR–βarr1 complex exhibits a tail engagement mode.<sup>2</sup> It remains unclear whether the core conformation is a characteristic of class A receptors in engaging βarr1.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"39 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850805","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}
Cell ResearchPub Date : 2025-08-06DOI: 10.1038/s41422-025-01146-z
Mingqian Huang, Mengqi Chen, Gege Yuan, Yiqiang Cui, Bin Shen, Zhaode Liu, Bohang Zhang, Junqing Chen, Dingdong Chen, Shuangshuang Qiu, Yichun Zhang, Li Liu, Lianju Qin, Yunfei Zhu, Jiayin Liu, Hao Zhang, Jun Wu, Yan Yuan, Jiahao Sha
{"title":"Establishment of human gastrulating stem cells with the capacity of stable differentiation into multiple gastrulating cell types","authors":"Mingqian Huang, Mengqi Chen, Gege Yuan, Yiqiang Cui, Bin Shen, Zhaode Liu, Bohang Zhang, Junqing Chen, Dingdong Chen, Shuangshuang Qiu, Yichun Zhang, Li Liu, Lianju Qin, Yunfei Zhu, Jiayin Liu, Hao Zhang, Jun Wu, Yan Yuan, Jiahao Sha","doi":"10.1038/s41422-025-01146-z","DOIUrl":"10.1038/s41422-025-01146-z","url":null,"abstract":"Pluripotent stem cells (PSCs) have been derived from various species, but most culture systems stabilize only a single PSC type. By contrast, epiblast cells in vivo exist along a continuum and interact dynamically with both embryonic and extraembryonic cells, interactions missing in standard PSC cultures. This absence limits the self-organizing potential of PSCs and leads to disorganized tissue formation in teratomas. To address this, we developed a unified culture system that supports the stable differentiation of epiblast-like cells into multiple key human gastrulating cell types, collectively called human gastrulating stem cells (hGaSCs). hGaSCs, composed of endoderm-like, mesoderm-like, ectoderm-like, amnion ectoderm-like, and primordial germ cell-like cells, maintain a stable balance during long-term culture. In 3D culture, hGaSCs self-assemble into gastruloid-like structures (hGaSC-gastruloids) that model aspects of a Carnegie Stage 7 human embryo, including gastrulation and germ layer specification. Using hGaSC-gastruloids, we modeled the effects of valproic acid (VPA) on human gastrulation and uncovered molecular pathways underlying VPA-induced malformations. When transplanted into the seminiferous tubules, hGaSCs formed embryo-like structures, progressing through fetal tissue and organ development, unlike the disorganized growth seen in teratomas. In conclusion, hGaSCs provide a versatile platform to study human gastrulation, early organogenesis, developmental defects, and drug teratogenicity, with promising applications in tissue and organ generation from cultured stem cells.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 10","pages":"719-734"},"PeriodicalIF":25.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786740","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}
Cell ResearchPub Date : 2025-08-01DOI: 10.1038/s41422-025-01159-8
Chin Wei Brian Leung, Fumiko Esashi
{"title":"Centromeres as minefields: host–virus warfare","authors":"Chin Wei Brian Leung, Fumiko Esashi","doi":"10.1038/s41422-025-01159-8","DOIUrl":"https://doi.org/10.1038/s41422-025-01159-8","url":null,"abstract":"<p><b>Nuclear cGAS acts as a vital line of defense against DNA virus infections. In a recent</b> <b><i>Cell</i></b> <b>paper, Lahaye and colleagues uncover a novel mechanism in which nuclear cGAS detects viral infection, triggered by the amplification of centromeric DNA.</b></p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"17 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755722","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}
Cell ResearchPub Date : 2025-08-01DOI: 10.1038/s41422-025-01160-1
Bianca Calí, Andrea Alimonti
{"title":"Neutrophil maturation holds the secret to human tumor suppression","authors":"Bianca Calí, Andrea Alimonti","doi":"10.1038/s41422-025-01160-1","DOIUrl":"10.1038/s41422-025-01160-1","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 9","pages":"619-620"},"PeriodicalIF":25.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01160-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755723","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}