{"title":"Structurally conserved human anti-A35 antibodies protect mice and macaques from mpox virus infection","authors":"Bin Ju, Congcong Liu, Jingjing Zhang, Yaning Li, Haonan Yang, Bing Zhou, Baoying Huang, Jianrong Ma, Jiahan Lu, Lin Cheng, Zhe Cong, Lin Zhu, Tianhao Shi, Yuehong Sun, Na Li, Ting Chen, Miao Wang, Shilong Tang, Xiangyang Ge, Juanjuan Zhao, Zheng Zhang","doi":"10.1016/j.cell.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.005","url":null,"abstract":"The A35 protein, expressed on the enveloped virion of monkeypox (mpox) virus (MPXV), is essential for viral infection and spread within the host, making it an effective antiviral target. In this study, we demonstrated two human anti-A35 monoclonal antibodies (mAbs) displayed potential protection against MPXV in CAST/EiJ mice and rhesus macaques. Using cryo-electron microscopy, we determined two high-resolution structures of the A35 dimer in complex with the fragment of antigen binding of mAb 975 or mAb 981, revealing detailed interactions at the antigen-antibody interfaces. Structural analysis showed that these structurally conserved mAbs bind to a groove region at the interface of A35 dimer. Overall, we provided a proof of concept for a single administration of anti-A35 mAbs mitigating the pathogenic effects of MPXV infection in rhesus macaques. These human-derived mAbs could be served as antibody drug candidates, and their binding models to the A35 dimer will provide valuable insights for future vaccine design.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"127 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900348","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.08.004
Raianna F. Fantin, Meng Yuan, Seok-Chan Park, Bailey Bozarth, Hallie Cohn, Maxinne Ignacio, Patricia Earl, Alesandro Civljak, Gabriel Laghlali, Ding Zhang, Xueyong Zhu, Jameson Crandell, Valter Monteiro, Jordan J. Clark, Catherine Cotter, Martin Burkhardt, Gagandeep Singh, Prajakta Warang, Juan García-Bernalt Diego, Komal Srivastava, Camila H. Coelho
{"title":"Human monoclonal antibodies targeting A35 protect from death caused by mpox","authors":"Raianna F. Fantin, Meng Yuan, Seok-Chan Park, Bailey Bozarth, Hallie Cohn, Maxinne Ignacio, Patricia Earl, Alesandro Civljak, Gabriel Laghlali, Ding Zhang, Xueyong Zhu, Jameson Crandell, Valter Monteiro, Jordan J. Clark, Catherine Cotter, Martin Burkhardt, Gagandeep Singh, Prajakta Warang, Juan García-Bernalt Diego, Komal Srivastava, Camila H. Coelho","doi":"10.1016/j.cell.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.004","url":null,"abstract":"The 2022 mpox outbreak highlighted the serious threat of monkeypox virus (MPXV), yet effective treatments are lacking. From an mpox-convalescent individual, we identified three high-affinity human monoclonal antibodies (mAbs) (named EV35-2, EV35-6, and EV35-7) that target the A35 protein in MPXV. These antibodies block viral spread <em>in vitro</em> and protect mice against lethal MPXV and vaccinia virus infection via both Fc-dependent and independent mechanisms. Levels of serum antibodies targeting the same epitopes are increased in mpox-convalescent humans, and higher levels of these antibodies in the sera are linked to shorter symptom duration and no hospitalization. Systems-level multivariate analysis indicated that mpox-convalescent serum antibodies targeting the same epitopic region as these three mAbs may function cooperatively, with additive associations to clinical protection. Two of the antibodies use a conserved IGHD2-21-encoded CxGGDCx motif in their CDRH3 region to bind a highly conserved poxvirus epitope. These findings establish A35 as a critical therapeutic target and highlight A35-specific mAbs as promising candidates for next-generation orthopoxvirus treatments.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900349","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.08.001
Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q. Balaban
{"title":"Uncovering phenotypic inheritance from single cells with Microcolony-seq","authors":"Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q. Balaban","doi":"10.1016/j.cell.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.001","url":null,"abstract":"Uncovering phenotypic heterogeneity is fundamental to understanding processes such as development and stress responses. Due to the low mRNA abundance in single bacteria, determining biologically relevant heterogeneity remains a challenge. Using Microcolony-seq, a methodology that captures inherited heterogeneity by analyzing microcolonies originating from single bacterial cells, we uncover the ubiquitous ability of bacteria to maintain long-term inheritance of the host environment. Notably, we observe that growth to stationary phase erases the epigenetic inheritance. By leveraging this memory within each microcolony, Microcolony-seq combines bulk RNA sequencing (RNA-seq) with whole-genome sequencing and phenotypic assays to detect the distinct subpopulations and their fitness advantages. Applying this directly to infected human samples enables us to uncover a wealth of diverse inherited phenotypes. Our observations suggest that bacterial memory may be a widespread phenomenon in both Gram-negative and Gram-positive bacteria. Microcolony-seq provides potential targets for the rational design of therapies with the power to simultaneously target the coexisting subpopulations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"22 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900351","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}
CellPub Date : 2025-08-26DOI: 10.1016/j.cell.2025.07.042
Emily Grist, Peter Dutey-Magni, Marina A. Parry, Larissa Mendes, Ashwin Sachdeva, James A. Proudfoot, Anis A. Hamid, Mazlina Ismail, Sarah Howlett, Stefanie Friedrich, Lia DePaula Oliveira, Laura Murphy, Christopher Brawley, Oluwademilade Dairo, Sharanpreet Lall, Yang Liu, Daniel Wetterskog, Anna Wingate, Karolina Nowakowska, Leila Zakka, Gerhardt Attard
{"title":"Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers","authors":"Emily Grist, Peter Dutey-Magni, Marina A. Parry, Larissa Mendes, Ashwin Sachdeva, James A. Proudfoot, Anis A. Hamid, Mazlina Ismail, Sarah Howlett, Stefanie Friedrich, Lia DePaula Oliveira, Laura Murphy, Christopher Brawley, Oluwademilade Dairo, Sharanpreet Lall, Yang Liu, Daniel Wetterskog, Anna Wingate, Karolina Nowakowska, Leila Zakka, Gerhardt Attard","doi":"10.1016/j.cell.2025.07.042","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.042","url":null,"abstract":"Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic). Tumor androgen receptor signaling is associated with longer survival, whereas increased proliferation predicted shorter survival. In a pre-specified analysis, the previously identified decipher RNA signature was both prognostic and predicted survival benefit from docetaxel for metastatic cancers (biomarker-docetaxel interaction <em>p</em> = 0.039). Additionally, transcriptome-based classification of PTEN inactivation identified tumors more likely to have PTEN protein loss (<em>p</em> = 4 × 10<sup>−37</sup>) and metabolically perturbed metastatic cancers that had shorter survival with hormone therapies (<em>p</em> < 0.001) but exhibited docetaxel sensitivity (biomarker-docetaxel interaction <em>p</em> = 0.002). Transcriptome classifiers predict docetaxel benefit and could be clinically implemented for improved patient management.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"32 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906472","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}
CellPub Date : 2025-08-25DOI: 10.1016/j.cell.2025.07.039
Kevin C. Allan, Jesse J. Zhan, Andrew R. Morton, Erin F. Cohn, Marissa A. Scavuzzo, Anushka Nikhil, Matthew S. Elitt, Benjamin L.L. Clayton, Lucille R. Hu, H. Elizabeth Shick, Jost K. Vrabic, Hannah E. Olsen, Daniel C. Factor, Jonathan E. Henninger, Gemma Bachmann, Berit E. Powers, Richard A. Young, Charles Y. Lin, Peter C. Scacheri, Tyler E. Miller, Paul J. Tesar
{"title":"Transient gene melting governs the timing of oligodendrocyte maturation","authors":"Kevin C. Allan, Jesse J. Zhan, Andrew R. Morton, Erin F. Cohn, Marissa A. Scavuzzo, Anushka Nikhil, Matthew S. Elitt, Benjamin L.L. Clayton, Lucille R. Hu, H. Elizabeth Shick, Jost K. Vrabic, Hannah E. Olsen, Daniel C. Factor, Jonathan E. Henninger, Gemma Bachmann, Berit E. Powers, Richard A. Young, Charles Y. Lin, Peter C. Scacheri, Tyler E. Miller, Paul J. Tesar","doi":"10.1016/j.cell.2025.07.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.039","url":null,"abstract":"Cellular maturation is a crucial step for tissue formation and function, distinct from the initial steps of differentiation and cell fate specification. In the central nervous system, failure of oligodendrocyte maturation is linked to diseases such as multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After progenitor cells differentiate into immature oligodendrocytes, the transcription factor SOX6 redistributes from super-enhancers to cluster across specific gene bodies. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turn off upon maturation. Suppression of SOX6 deactivates these immaturity loci, accelerating the transition to mature, myelinating oligodendrocytes. Notably, cells harboring this immature SOX6 gene signature are enriched in multiple sclerosis patient brains and antisense oligonucleotide-mediated <em>Sox6</em> knockdown drives oligodendrocyte maturation in mice. Our findings establish SOX6 as a key regulator of oligodendrocyte maturation and highlight its potential as a therapeutic target to promote myelination in disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900357","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}
CellPub Date : 2025-08-21DOI: 10.1016/j.cell.2025.07.020
Douglas N Robinson
{"title":"Targeting myosin II to alter the disease course of challenging diseases.","authors":"Douglas N Robinson","doi":"10.1016/j.cell.2025.07.020","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.020","url":null,"abstract":"<p><p>In this issue of Cell, Kenchappa et al. and Radnai et al. report the development of selective non-muscle myosin II inhibitors that show therapeutic potential in glioblastoma and methamphetamine use disorder, opening new avenues for targeting cell mechanobiology in challenging diseases.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":"188 17","pages":"4475-4477"},"PeriodicalIF":42.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944184","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}
CellPub Date : 2025-08-21DOI: 10.1016/j.cell.2025.07.037
Kevin K Yang, Ava P Amini
{"title":"Simplifying protein engineering with deep learning.","authors":"Kevin K Yang, Ava P Amini","doi":"10.1016/j.cell.2025.07.037","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.037","url":null,"abstract":"<p><p>When it comes to deep learning for protein engineering, there is strength in simplicity. In this issue of Cell, through thoughtful deployment of existing fixed-backbone sequence design models, Caixia Gao and colleagues engineer diverse genome editing systems with improved functionality, enabling powerful capabilities in fine-grained and large-scale genome editing as demonstrated through strong experimental validation.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":"188 17","pages":"4477-4479"},"PeriodicalIF":42.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944243","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}
CellPub Date : 2025-08-21DOI: 10.1016/j.cell.2025.06.044
Daniel Boehmer, Ivan Zanoni
{"title":"Interferons in health and disease.","authors":"Daniel Boehmer, Ivan Zanoni","doi":"10.1016/j.cell.2025.06.044","DOIUrl":"https://doi.org/10.1016/j.cell.2025.06.044","url":null,"abstract":"<p><p>Interferons (IFNs) are signaling proteins that play fundamental roles during health and disease. Although types I, II, and III IFNs are structurally and functionally different, all IFNs signal via an intricate network of Janus kinases, named after the Roman god of time and duality. IFNs are characterized by activities that vary over time and can lead to opposing outcomes. IFNs have protective roles during bacterial, viral, and fungal infections but can also drive numerous inflammatory and autoimmune diseases. In this review, we provide an overview of the cellular and molecular mechanisms governing IFN induction and responses, emphasizing their roles in infections, tumorigenesis, and inflammatory, autoimmune, and genetic diseases, with particular attention to mucosal tissues. Overall, we spotlight how the balanced production of distinct members of the IFN families over time is necessary to exert their protective functions and the detrimental consequences for the host when this balance is lost.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":"188 17","pages":"4480-4504"},"PeriodicalIF":42.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944229","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":"Shank3 oligomerization governs material properties of the postsynaptic density condensate and synaptic plasticity.","authors":"Bowen Jia, Zeyu Shen, Shihan Zhu, Jingguo Huang, Zhitao Liao, Shuaizhu Zhao, Hao Li, Shiwen Chen, Yang Xu, Yu Wang, Haitang Peng, Guanhua Bai, Youming Lu, Penger Tong, Wucheng Tao, Mingjie Zhang","doi":"10.1016/j.cell.2025.07.047","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.047","url":null,"abstract":"<p><p>Cells contain numerous types of membraneless organelles or biological condensates formed via phase separation. Cellular biological condensates have broad material properties ranging from Newtonian fluids to elastic solids. How the material property of a biological condensate is regulated for cellular functions is poorly understood. Here, we discovered that, like native postsynaptic densities (PSDs), the reconstituted PSD condensate forms a soft glass material without signs of irreversible amyloid structure formation. Such glass-like PSD condensate formation is based on percolation of the PSD protein network via specific and multivalent interactions among scaffold proteins. Disruption of Shank3 SAM domain-mediated oligomerization, one type of SHANK3 mutation observed in Phelan-McDermid syndrome patients, softened the PSD condensate by weakening its network percolation, impaired synaptic transmission and plasticity, and caused autistic-like behavior in mice. Thus, our study suggests that the material properties of the PSD condensate are critical for learning and memory mediated by neuronal synapses.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944187","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}
CellPub Date : 2025-08-18DOI: 10.1016/j.cell.2025.07.043
Sven M Lange, Jeremy A Bennett, Robyn J Eisert, Alan Brown
{"title":"A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia.","authors":"Sven M Lange, Jeremy A Bennett, Robyn J Eisert, Alan Brown","doi":"10.1016/j.cell.2025.07.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.07.043","url":null,"abstract":"<p><p>The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis and demonstrate how structural changes in IFT trains achieve cargo selectivity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944203","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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