CellPub Date : 2025-10-02DOI: 10.1016/j.cell.2025.08.026
Lesia Rodriguez, Lukáš Fiedler, Minxia Zou, Caterina Giannini, Aline Monzer, Dmitrii Vladimirtsev, Marek Randuch, Yongfan Yu, Zuzana Gelová, Inge Verstraeten, Jakub Hajný, Meng Chen, Shutang Tan, Lukas Hoermayer, Lanxin Li, Maria Mar Marques-Bueno, Zainab Quddoos, Gergely Molnár, Ivan Kulich, Yvon Jaillais, Jiří Friml
{"title":"ABP1/ABL3-TMK1 cell-surface auxin signaling targets PIN2-mediated auxin fluxes for root gravitropism","authors":"Lesia Rodriguez, Lukáš Fiedler, Minxia Zou, Caterina Giannini, Aline Monzer, Dmitrii Vladimirtsev, Marek Randuch, Yongfan Yu, Zuzana Gelová, Inge Verstraeten, Jakub Hajný, Meng Chen, Shutang Tan, Lukas Hoermayer, Lanxin Li, Maria Mar Marques-Bueno, Zainab Quddoos, Gergely Molnár, Ivan Kulich, Yvon Jaillais, Jiří Friml","doi":"10.1016/j.cell.2025.08.026","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.026","url":null,"abstract":"Phytohormone auxin and its directional transport mediate much of the remarkably plastic development of higher plants. Positive feedback between auxin signaling and transport is a prerequisite for (1) self-organizing processes, including vascular tissue formation, and (2) directional growth responses such as gravitropism. Here, we identify a mechanism by which auxin signaling directly targets PIN auxin transporters. Via the cell-surface AUXIN-BINDING PROTEIN1 (ABP1)-TRANSMEMBRANE KINASE 1 (TMK1) receptor module, auxin rapidly induces phosphorylation and thus stabilization of PIN2. Following gravistimulation, initial auxin asymmetry activates autophosphorylation of the TMK1 kinase. This induces TMK1 interaction with and phosphorylation of PIN2, stabilizing PIN2 at the lower root side, thus reinforcing asymmetric auxin flow for root bending. Upstream of TMK1 in this regulation, ABP1 acts redundantly with the root-expressed ABP1-LIKE 3 (ABL3) auxin receptor. Such positive feedback between cell-surface auxin signaling and PIN-mediated polar auxin transport is fundamental for robust root gravitropism and presumably for other self-organizing developmental phenomena.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"114 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204027","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 : 2025-10-02DOI: 10.1016/j.cell.2025.08.037
Kyle Coleman, Nicholas P. Tatonetti
{"title":"Decoding Alzheimer’s disease at the cellular level reveals promising combination therapy","authors":"Kyle Coleman, Nicholas P. Tatonetti","doi":"10.1016/j.cell.2025.08.037","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.037","url":null,"abstract":"Alzheimer’s disease (AD) has long resisted effective treatments due to its pathological heterogeneity and cell-type-specific regulatory changes. In this issue of <em>Cell</em>, Li et al. leverage single-cell RNA sequencing and drug repurposing to propose a promising combination therapy, validated through real-world evidence and mouse models, that targets multiple AD-relevant cell types.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"60 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204028","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 : 2025-10-02DOI: 10.1016/j.cell.2025.08.033
Cecilia Xi Zhang, Ruby Yun-Ju Huang, Guojun Sheng, Jean Paul Thiery
{"title":"Epithelial-mesenchymal transition","authors":"Cecilia Xi Zhang, Ruby Yun-Ju Huang, Guojun Sheng, Jean Paul Thiery","doi":"10.1016/j.cell.2025.08.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.033","url":null,"abstract":"Epithelial-mesenchymal transition (EMT) is a fundamental mechanism involved in the morphogenesis of metazoans. Through this evolutionarily conserved multi-stage process, cells acquire quasi-epithelial to multiple intermediate morphologies with epithelial and mesenchymal attributes, rarely reaching a complete mesenchymal phenotype. Complex evolutionary-conserved morphogenetic movements in gastrulation are described extensively, as they exemplify the extent of epithelial cell plasticity in the animal kingdom. Nonetheless, a single-gene knockout can modify the mode of gastrulation while achieving the same body plan. Numerous interconnected mechanisms drive different degrees of EMT, including surface receptor signaling, metabolism, and epigenetics. EMT is reactivated in adult tissues during repair and disease, particularly in cancer initiation, progression to metastasis, and refractoriness to treatment. EMT also contributes to dormancy and drug tolerance, leading to minimal residual disease at the origin of recurrences. Multiple EMT states coexist in tumors, creating a dynamic ecosystem for generating an inflammatory microenvironment, stemness, invasion, and metastasis. This review provides an in-depth description of these aspects along with recent controversies and offers new opportunities to further explore the multiple functions of EMT. Examining the potential attributes of EMT in tissue repair, fibrosis, and cancer progression can provide new opportunities for therapeutic intervention.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204029","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 : 2025-10-01DOI: 10.1016/j.cell.2025.09.006
Yubao Cheng, Shengyuan Dang, Yuan Zhang, Yanbo Chen, Ruihuan Yu, Miao Liu, Shengyan Jin, Ailin Han, Samuel Katz, Siyuan Wang
{"title":"Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution","authors":"Yubao Cheng, Shengyuan Dang, Yuan Zhang, Yanbo Chen, Ruihuan Yu, Miao Liu, Shengyan Jin, Ailin Han, Samuel Katz, Siyuan Wang","doi":"10.1016/j.cell.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.cell.2025.09.006","url":null,"abstract":"Recent breakthroughs in spatial transcriptomics technologies have enhanced our understanding of diverse cellular identities, spatial organizations, and functions. Yet existing spatial transcriptomics tools are still limited in either transcriptomic coverage or spatial resolution, hindering unbiased, hypothesis-free transcriptomic analyses at high spatial resolution. Here, we develop reverse-padlock amplicon-encoding fluorescence <em>in situ</em> hybridization (RAEFISH), an image-based spatial transcriptomics method with whole-genome coverage and single-molecule resolution in intact tissues. We demonstrate the spatial profiling of transcripts from 23,000 human or 22,000 mouse genes in single cells and tissue sections. Our analyses reveal transcript-specific subcellular localization, cell-type-specific and cell-type-invariant zonation-dependent transcriptomes, and gene programs underlying preferential cell-cell interactions. Finally, we further develop our technology for the direct spatial readout of guide RNAs (gRNAs) in an image-based, high-content CRISPR screen. Overall, these developments offer a broadly applicable technology that enables high-coverage, high-resolution spatial profiling of both long and short, native and engineered RNAs in many biomedical contexts.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195044","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":"Genomic atlas of 8,105 accessions reveals stepwise domestication, global dissemination, and improvement trajectories in soybean","authors":"Zhou Zhu, Yalin Wang, Shulin Liu, Shoudong Wang, Juxu Li, Chao Fang, Yucheng Liu, Xiaoyue Yang, Dongmei Tian, Shuhui Song, Zhixi Tian","doi":"10.1016/j.cell.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.09.007","url":null,"abstract":"After millennia of domestication, dissemination, and improvement, soybean has evolved into a globally significant leguminous crop. Addressing how soybeans adapt to diverse planting environments and breeding objectives will facilitate future breeding advancements. Here, we systematically investigated the genes under selection of 8,105 soybean accessions underlying domestication, dissemination, and improvement. The analyses revealed that black soybeans serve as a critical domestication intermediate, and soybean domestication traits were selected in a stepwise manner. Comparisons across accessions from diverse geographical areas and historical eras identified numerous selected genes that have contributed to trait enhancement and environmental adaptation during the global dissemination and unveiled a temporal shift of breeding priorities in soybean improvement in China. To highlight the allele utilization among soybean varieties, we constructed a variation map and quantitative trait nucleotide (QTN) library. Our findings provide valuable insights and serve as a critical resource for understanding soybean domestication and informing breeding strategies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195043","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 : 2025-09-30DOI: 10.1016/j.cell.2025.09.019
Marcel S. Woo, Johannes Brand, Lukas C. Bal, Manuela Moritz, Mark Walkenhorst, Vanessa Vieira, Inbal Ipenberg, Nicola Rothammer, Man Wang, Batuhan Dogan, Desirée Loreth, Christina Mayer, Darwin Nagel, Ingrid Wagner, Lena Kristina Pfeffer, Peter Landgraf, Marco van Ham, Kuno M.-J. Mattern, Ingo Winschel, Noah Frantz, Manuel A. Friese
{"title":"The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis","authors":"Marcel S. Woo, Johannes Brand, Lukas C. Bal, Manuela Moritz, Mark Walkenhorst, Vanessa Vieira, Inbal Ipenberg, Nicola Rothammer, Man Wang, Batuhan Dogan, Desirée Loreth, Christina Mayer, Darwin Nagel, Ingrid Wagner, Lena Kristina Pfeffer, Peter Landgraf, Marco van Ham, Kuno M.-J. Mattern, Ingo Winschel, Noah Frantz, Manuel A. Friese","doi":"10.1016/j.cell.2025.09.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.09.019","url":null,"abstract":"(Cell <em>188</em>, 4567–4585.e1–e32; August 21, 2025)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"100 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189390","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 : 2025-09-30DOI: 10.1016/j.cell.2025.09.005
Peter H. Culviner, Abigail M. Frey, Qingyun Liu, Dang Thi Minh Ha, Phan Vuong Khac Thai, Do Dang Anh Thu, Nguyen Le Quang, Roger Calderon, Leonid Lecca, Maxine Caws, Sarah J. Dunstan, Megan B. Murray, Nguyen Thuy Thuong Thuong, Sarah M. Fortune
{"title":"Evolution of Mycobacterium tuberculosis transcription regulation is associated with increased transmission and drug resistance","authors":"Peter H. Culviner, Abigail M. Frey, Qingyun Liu, Dang Thi Minh Ha, Phan Vuong Khac Thai, Do Dang Anh Thu, Nguyen Le Quang, Roger Calderon, Leonid Lecca, Maxine Caws, Sarah J. Dunstan, Megan B. Murray, Nguyen Thuy Thuong Thuong, Sarah M. Fortune","doi":"10.1016/j.cell.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.09.005","url":null,"abstract":"<em>Mycobacterium tuberculosis</em> (Mtb) has co-evolved with humans for thousands of years and is characterized by variation in virulence, transmissibility, and disease phenotypes. To identify bacterial contributors to phenotypic diversity, we developed new RNA sequencing (RNA-seq) and phylogenomic tools to capture hundreds of Mtb isolate transcriptomes, link transcriptional and genetic variation, and find associations between variants and epidemiologic traits. Across 274 Mtb clinical isolates, we uncovered unexpected diversity in virulence gene expression, which we linked to known and unknown regulators. Surprisingly, we found that many isolates harbor variants associated with decreased expression of EsxA (Esat6) and EsxB (Cfp10), which are virulence effectors, dominant T cell antigens, and immunodiagnostic targets. Across >55,000 isolates, these variants associate with increased transmissibility, especially in drug-resistant Mtb strains. Our data suggest expression of Mtb virulence genes is evolving in response to drug-linked pressure, raising concerns about use of these targets in immunodiagnostics and next-generation vaccines.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"104 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189201","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":"Functional RNA splitting drove the evolutionary emergence of type V CRISPR-Cas systems from transposons","authors":"Shuai Jin, Zixu Zhu, Yunjia Li, Shouyue Zhang, Yijing Liu, Danyuan Li, Yuanqing Li, Yingfeng Luo, Zhiheng Cheng, Kevin Tianmeng Zhao, Qiang Gao, Guanglei Yang, Hongchao Li, Ronghong Liang, Rui Zhang, Jin-Long Qiu, Yong E. Zhang, Jun-Jie Gogo Liu, Caixia Gao","doi":"10.1016/j.cell.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.09.004","url":null,"abstract":"Transposon-encoded TnpB nucleases gave rise to type V CRISPR-Cas12 effectors through multiple independent domestication events. These systems use different RNA molecules as guides for DNA targeting: transposon-derived right-end RNAs (reRNAs or omega RNAs) for TnpB and CRISPR RNAs for type V CRISPR-Cas systems. However, the molecular mechanisms bridging transposon activity and CRISPR immunity remain unclear. We identify TranCs (transposon-CRISPR intermediates) derived from distinct IS605- or IS607-TnpB lineages. TranCs utilize both CRISPR RNAs and reRNAs to direct DNA cleavage. The cryoelectron microscopy (cryo-EM) structure of LaTranC from <em>Lawsonibacter sp.</em> closely resembles that of the ISDra2 TnpB complex; however, unlike a single-molecule reRNA, the LaTranC guide RNA is functionally split into a tracrRNA and crRNA. An engineered RNA split of ISDra2 TnpB enabled activity with a CRISPR array. These findings indicate that functional RNA splitting was the primary molecular event driving the emergence of diverse type V CRISPR-Cas systems from transposons.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183022","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 : 2025-09-26DOI: 10.1016/j.cell.2025.08.039
Jan N. Hansen, Huangqingbo Sun, Konstantin Kahnert, Eini Westenius, Alexandra Johannesson, Carmela Villegas, Trang Le, Kalliopi Tzavlaki, Casper Winsnes, Emmie Pohjanen, Anna Mäkiniemi, Jenny Fall, Frederic Ballllosera Navarro, Anna Bäckström, Cecilia Lindskog, Fredric Johansson, Kalle von Feilitzen, Angelica M. Delgado-Vega, Anna Martinez Casals, Diana Mahdessian, Emma Lundberg
{"title":"Intrinsic heterogeneity of primary cilia revealed through spatial proteomics","authors":"Jan N. Hansen, Huangqingbo Sun, Konstantin Kahnert, Eini Westenius, Alexandra Johannesson, Carmela Villegas, Trang Le, Kalliopi Tzavlaki, Casper Winsnes, Emmie Pohjanen, Anna Mäkiniemi, Jenny Fall, Frederic Ballllosera Navarro, Anna Bäckström, Cecilia Lindskog, Fredric Johansson, Kalle von Feilitzen, Angelica M. Delgado-Vega, Anna Martinez Casals, Diana Mahdessian, Emma Lundberg","doi":"10.1016/j.cell.2025.08.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.08.039","url":null,"abstract":"Primary cilia are critical organelles found on most human cells. Their dysfunction is linked to hereditary ciliopathies with a wide phenotypic spectrum. Despite their significance, the specific roles of cilia in different cell types remain poorly understood due to limitations in analyzing ciliary protein composition. We employed antibody-based spatial proteomics to expand the Human Protein Atlas to primary cilia. Our analysis identified the subciliary locations of 715 proteins across three cell lines, examining 128,156 individual cilia. We found that 69% of the ciliary proteome is cell-type specific, and 78% exhibited single-cilia heterogeneity. Our findings portray cilia as sensors tuning their proteome to effectively sense the environment and compute cellular responses. We reveal 91 cilia proteins and found a genetic candidate variant in <em>CREB3</em> in one clinical case with features overlapping ciliopathy phenotypes. This open, spatial cilia atlas advances research on cilia and ciliopathies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140596","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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