CellPub Date : 2025-02-20DOI: 10.1016/j.cell.2025.01.015
Artem Khan, Yuyang Liu, Mark Gad, Timothy C. Kenny, Kıvanç Birsoy
{"title":"Solute carriers: The gatekeepers of metabolism","authors":"Artem Khan, Yuyang Liu, Mark Gad, Timothy C. Kenny, Kıvanç Birsoy","doi":"10.1016/j.cell.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.015","url":null,"abstract":"Solute carrier (SLC) proteins play critical roles in maintaining cellular and organismal homeostasis by transporting small molecules and ions. Despite a growing body of research over the past decade, physiological substrates and functions of many SLCs remain elusive. This perspective outlines key challenges in studying SLC biology and proposes an evidence-based framework for defining SLC substrates. To accelerate the deorphanization process, we explore systematic technologies, including human genetics, biochemistry, and computational and structural approaches. Finally, we suggest directions to better understand SLC functions beyond substrate identification in physiology and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"50 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463096","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 : 2025-02-20DOI: 10.1016/j.cell.2024.11.034
Jessica Pérez-Sancho, Marija Smokvarska, Gwennogan Dubois, Marie Glavier, Sujith Sritharan, Tatiana S. Moraes, Hortense Moreau, Victor Dietrich, Matthieu P. Platre, Andrea Paterlini, Ziqiang P. Li, Laetitia Fouillen, Magali S. Grison, Pepe Cana-Quijada, Françoise Immel, Valerie Wattelet, Mathieu Ducros, Lysiane Brocard, Clément Chambaud, Yongming Luo, Emmanuelle M. Bayer
{"title":"Plasmodesmata act as unconventional membrane contact sites regulating intercellular molecular exchange in plants","authors":"Jessica Pérez-Sancho, Marija Smokvarska, Gwennogan Dubois, Marie Glavier, Sujith Sritharan, Tatiana S. Moraes, Hortense Moreau, Victor Dietrich, Matthieu P. Platre, Andrea Paterlini, Ziqiang P. Li, Laetitia Fouillen, Magali S. Grison, Pepe Cana-Quijada, Françoise Immel, Valerie Wattelet, Mathieu Ducros, Lysiane Brocard, Clément Chambaud, Yongming Luo, Emmanuelle M. Bayer","doi":"10.1016/j.cell.2024.11.034","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.034","url":null,"abstract":"Membrane contact sites (MCSs) are fundamental for intracellular communication, but their role in intercellular communication remains unexplored. We show that in plants, plasmodesmata communication bridges function as atypical endoplasmic reticulum (ER)-plasma membrane (PM) tubular MCSs, operating at cell-cell interfaces. Similar to other MCSs, ER-PM apposition is controlled by a protein-lipid tethering complex, but uniquely, this serves intercellular communication. Combining high-resolution microscopy, molecular dynamics, and pharmacological and genetic approaches, we show that cell-cell trafficking is modulated through the combined action of multiple C2 domains transmembrane domain proteins (MCTPs) 3, 4, and 6 ER-PM tethers and phosphatidylinositol-4-phosphate (PI4P) lipid. Graded PI4P amounts regulate MCTP docking to the PM, their plasmodesmata localization, and cell-cell permeability. SAC7, an ER-localized PI4P-phosphatase, regulates MCTP4 accumulation at plasmodesmata and modulates cell-cell trafficking capacity in a cell-type-specific manner. Our findings expand MCS functions in information transmission from intracellular to intercellular cellular activities.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"29 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463126","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 : 2025-02-20DOI: 10.1016/j.cell.2025.01.033
Nicholas A. Prescott, Tracy Biaco, Andrés Mansisidor, Yaron Bram, Justin Rendleman, Sarah C. Faulkner, Abigail A. Lemmon, Christine Lim, Rachel Tiersky, Eralda Salataj, Liliana Garcia-Martinez, Rodrigo L. Borges, Lluis Morey, Pierre-Jacques Hamard, Richard P. Koche, Viviana I. Risca, Robert E. Schwartz, Yael David
{"title":"A nucleosome switch primes hepatitis B virus infection","authors":"Nicholas A. Prescott, Tracy Biaco, Andrés Mansisidor, Yaron Bram, Justin Rendleman, Sarah C. Faulkner, Abigail A. Lemmon, Christine Lim, Rachel Tiersky, Eralda Salataj, Liliana Garcia-Martinez, Rodrigo L. Borges, Lluis Morey, Pierre-Jacques Hamard, Richard P. Koche, Viviana I. Risca, Robert E. Schwartz, Yael David","doi":"10.1016/j.cell.2025.01.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.033","url":null,"abstract":"Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings <em>in situ</em> and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"20 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463095","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 : 2025-02-20DOI: 10.1016/j.cell.2025.01.005
Jacqueline Cordes, Shubo Zhao, Carla M. Engel, Julian Stingele
{"title":"Cellular responses to RNA damage","authors":"Jacqueline Cordes, Shubo Zhao, Carla M. Engel, Julian Stingele","doi":"10.1016/j.cell.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.005","url":null,"abstract":"RNA plays a central role in protein biosynthesis and performs diverse regulatory and catalytic functions, making it essential for all processes of life. Like DNA, RNA is constantly subjected to damage from endogenous and environmental sources. However, while the DNA damage response has been extensively studied, it was long assumed that RNA lesions are relatively inconsequential due to the transient nature of most RNA molecules. Here, we review recent studies that challenge this view by revealing complex RNA damage responses that determine survival when cells are exposed to nucleic acid-damaging agents and promote the resolution of RNA lesions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"44 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463097","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 : 2025-02-20DOI: 10.1016/j.cell.2025.01.011
Victoria N. Parikh, Sharlene M. Day, Neal K. Lakdawala, Eric D. Adler, Iacopo Olivotto, Christine E. Seidman, Carolyn Y. Ho
{"title":"Advances in the study and treatment of genetic cardiomyopathies","authors":"Victoria N. Parikh, Sharlene M. Day, Neal K. Lakdawala, Eric D. Adler, Iacopo Olivotto, Christine E. Seidman, Carolyn Y. Ho","doi":"10.1016/j.cell.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.011","url":null,"abstract":"Cardiomyopathies are primary disorders of the heart muscle. Three key phenotypes have been defined, based on morphology and arrhythmia burden: hypertrophic cardiomyopathy (HCM), with thickened heart muscle and diastolic dysfunction; dilated cardiomyopathy (DCM), with left ventricular enlargement and systolic dysfunction; and arrhythmogenic cardiomyopathy (ACM), with right, left, or biventricular involvement and arrhythmias out of proportion to systolic dysfunction. Genetic discoveries of the molecular basis of disease are paving the way for greater precision in diagnosis and management and revealing mechanisms that account for distinguishing clinical features. This deeper understanding has propelled the development of new treatments for cardiomyopathies: disease-specific, mechanistically based medicines that counteract pathophysiology, and emergent gene therapies that aim to intercept disease progression and restore cardiac physiology. Together, these discoveries have advanced fundamental insights into cardiac biology and herald a new era for patients with cardiomyopathy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"29 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463098","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 : 2025-02-19DOI: 10.1016/j.cell.2025.01.037
Xiaomin Ou, Chengying Ma, Dongjie Sun, Jinkun Xu, Yang Wang, Xiaofei Wu, Dali Wang, Song Yang, Ning Gao, Chen Song, Long Li
{"title":"SecY translocon chaperones protein folding during membrane protein insertion","authors":"Xiaomin Ou, Chengying Ma, Dongjie Sun, Jinkun Xu, Yang Wang, Xiaofei Wu, Dali Wang, Song Yang, Ning Gao, Chen Song, Long Li","doi":"10.1016/j.cell.2025.01.037","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.037","url":null,"abstract":"The Sec translocon is vital for guiding membrane protein insertion into lipid bilayers. The insertion and folding processes of membrane proteins are poorly understood. Here, we report cryo-electron microscopy structures of multi-spanning membrane proteins inserting through the SecY channel, the Sec translocon in prokaryotes. The high-resolution structures illustrate how bulky amino acids pass the narrow channel restriction. Comparison of different translocation states reveals that the cytoplasmic and extracellular cavities of the channel create distinct environments for promoting the unfolding and folding of transmembrane segments (TMs), respectively. Released substrate TMs are either flexible or stabilized by an unexpected hydrophilic groove between TM3 and TM4 of SecY. Disruption of the groove causes global defects in the folding of the membrane proteome. These findings demonstrate that beyond its role as a passive protein-conducting channel, the SecY translocon actively serves as a chaperone, employing multiple mechanisms to promote membrane protein insertion and folding.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"64 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451841","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 : 2025-02-19DOI: 10.1016/j.cell.2025.01.036
Jacob Parres-Gold, Matthew Levine, Benjamin Emert, Andrew Stuart, Michael B. Elowitz
{"title":"Contextual computation by competitive protein dimerization networks","authors":"Jacob Parres-Gold, Matthew Levine, Benjamin Emert, Andrew Stuart, Michael B. Elowitz","doi":"10.1016/j.cell.2025.01.036","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.036","url":null,"abstract":"Many biological signaling pathways employ proteins that competitively dimerize in diverse combinations. These dimerization networks can perform biochemical computations in which the concentrations of monomer inputs determine the concentrations of dimer outputs. Despite their prevalence, little is known about the range of input-output computations that dimerization networks can perform and how it depends on network size and connectivity. Using a systematic computational approach, we demonstrate that even small dimerization networks of 3–6 monomers are <em>expressive</em>, performing diverse multi-input computations. Further, dimerization networks are <em>versatile</em>, performing different computations when their protein components are expressed at different levels, such as in different cell types. Remarkably, individual networks with random interaction affinities, when large enough, can perform nearly all potential one-input network computations merely by tuning their monomer expression levels. Thus, even the simple process of competitive dimerization provides a powerful architecture for multi-input, cell-type-specific signal processing.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451839","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 : 2025-02-19DOI: 10.1016/j.cell.2025.01.032
Mateo Vélez-Fort, Lee Cossell, Laura Porta, Claudia Clopath, Troy W. Margrie
{"title":"Motor and vestibular signals in the visual cortex permit the separation of self versus externally generated visual motion","authors":"Mateo Vélez-Fort, Lee Cossell, Laura Porta, Claudia Clopath, Troy W. Margrie","doi":"10.1016/j.cell.2025.01.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.032","url":null,"abstract":"Knowing whether we are moving or something in the world is moving around us is possibly the most critical sensory discrimination we need to perform. How the brain and, in particular, the visual system solves this motion-source separation problem is not known. Here, we find that motor, vestibular, and visual motion signals are used by the mouse primary visual cortex (VISp) to differentially represent the same visual flow information according to whether the head is stationary or experiencing passive versus active translation. During locomotion, we find that running suppresses running-congruent translation input and that translation signals dominate VISp activity when running and translation speed become incongruent. This cross-modal interaction between the motor and vestibular systems was found throughout the cortex, indicating that running and translation signals provide a brain-wide egocentric reference frame for computing the internally generated and actual speed of self when moving through and sensing the external world.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451840","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 : 2025-02-18DOI: 10.1016/j.cell.2025.01.034
Shai Zilberzwige-Tal, Han Altae-Tran, Soumya Kannan, Max E. Wilkinson, Samuel Chau-Duy-Tam Vo, Daniel Strebinger, KeHuan K. Edmonds, Chun-Chen Jerry Yao, Kepler S. Mears, Sergey A. Shmakov, Kira S. Makarova, Rhiannon K. Macrae, Eugene V. Koonin, Feng Zhang
{"title":"Reprogrammable RNA-targeting CRISPR systems evolved from RNA toxin-antitoxins","authors":"Shai Zilberzwige-Tal, Han Altae-Tran, Soumya Kannan, Max E. Wilkinson, Samuel Chau-Duy-Tam Vo, Daniel Strebinger, KeHuan K. Edmonds, Chun-Chen Jerry Yao, Kepler S. Mears, Sergey A. Shmakov, Kira S. Makarova, Rhiannon K. Macrae, Eugene V. Koonin, Feng Zhang","doi":"10.1016/j.cell.2025.01.034","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.034","url":null,"abstract":"Despite ongoing efforts to study CRISPR systems, the evolutionary origins giving rise to reprogrammable RNA-guided mechanisms remain poorly understood. Here, we describe an integrated sequence/structure evolutionary tracing approach to identify the ancestors of the RNA-targeting CRISPR-Cas13 system. We find that Cas13 likely evolved from AbiF, which is encoded by an abortive infection-linked gene that is stably associated with a conserved non-coding RNA (ncRNA). We further characterize a miniature Cas13, classified here as Cas13e, which serves as an evolutionary intermediate between AbiF and other known Cas13s. Despite this relationship, we show that their functions substantially differ. Whereas Cas13e is an RNA-guided RNA-targeting system, AbiF is a toxin-antitoxin (TA) system with an RNA antitoxin. We solve the structure of AbiF using cryoelectron microscopy (cryo-EM), revealing basic structural alterations that set Cas13s apart from AbiF. Finally, we map the key structural changes that enabled a non-guided TA system to evolve into an RNA-guided CRISPR system.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"51 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435503","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 : 2025-02-18DOI: 10.1016/j.cell.2025.01.042
Jing Chen, Wei Zhang, Yang Li, Chen Liu, Tianyi Dong, Huiyu Chen, Chunguang Wu, Jia Su, Bei Li, Wei Zhang, Ben Hu, Jingkun Jia, Cheng-Bao Ma, Yan Zhu, Xiangyang He, Ang Li, Kaiyi Pan, Haofeng Lin, Zishuo Guo, Cong Li, Zheng-Li Shi
{"title":"Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor","authors":"Jing Chen, Wei Zhang, Yang Li, Chen Liu, Tianyi Dong, Huiyu Chen, Chunguang Wu, Jia Su, Bei Li, Wei Zhang, Ben Hu, Jingkun Jia, Cheng-Bao Ma, Yan Zhu, Xiangyang He, Ang Li, Kaiyi Pan, Haofeng Lin, Zishuo Guo, Cong Li, Zheng-Li Shi","doi":"10.1016/j.cell.2025.01.042","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.042","url":null,"abstract":"Merbecoviruses comprise four viral species with remarkable genetic diversity: <em>MERS-related coronavirus</em>, <em>Tylonycteris</em> <em>bat coronavirus HKU4</em>, <em>Pipistrellus</em> <em>bat coronavirus HKU5</em>, and <em>Hedgehog coronavirus 1</em>. However, the potential human spillover risk of animal merbecoviruses remains to be investigated. Here, we reported the discovery of HKU5-CoV lineage 2 (HKU5-CoV-2) in bats that efficiently utilize human angiotensin-converting enzyme 2 (ACE2) as a functional receptor and exhibits a broad host tropism. Cryo-EM analysis of HKU5-CoV-2 receptor-binding domain (RBD) and human ACE2 complex revealed an entirely distinct binding mode compared with other ACE2-utilizing merbecoviruses with RBD footprint largely shared with ACE2-using sarbecoviruses and NL63. Structural and functional analyses indicate that HKU5-CoV-2 has a better adaptation to human ACE2 than lineage 1 HKU5-CoV. Authentic HKU5-CoV-2 infected human ACE2-expressing cell lines and human respiratory and enteric organoids. This study reveals a distinct lineage of HKU5-CoVs in bats that efficiently use human ACE2 and underscores their potential zoonotic risk.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435502","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}