Pub Date : 2026-01-07DOI: 10.1016/j.molcel.2025.12.016
Chan Liu, Yifan Zhang, Yilun Wang, Min Wu, Yunchao Li, Jiashuai Wei, Jiawen Shi, Rong Wang, Li Su, Tingting Yang, Jin Li, Junjie Xiao, Jianping Ding, Tianlong Zhang
Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.
{"title":"CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity","authors":"Chan Liu, Yifan Zhang, Yilun Wang, Min Wu, Yunchao Li, Jiashuai Wei, Jiawen Shi, Rong Wang, Li Su, Tingting Yang, Jin Li, Junjie Xiao, Jianping Ding, Tianlong Zhang","doi":"10.1016/j.molcel.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.12.016","url":null,"abstract":"Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"14 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907939","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}
Pub Date : 2025-12-22DOI: 10.1016/j.molcel.2025.12.002
Sonja Engler, Florent Delhommel, Christopher Dodt, Abraham Lopez, Ofrah Faust, Annika Elimelech, Valeria Napolitano, Grzegorz M. Popowicz, Rina Rosenzweig, Michael Sattler, Johannes Buchner
The Hsp90 molecular chaperone system is regulated by numerous co-chaperones that modulate its function. In Saccharomyces cerevisiae, most of these cofactors can be deleted without affecting viability. Of the three essential ones, only the function of Sgt1 has remained enigmatic. Our in vivo and in vitro experiments define key structural elements and determine the essential function of Sgt1 in the chaperoning of client proteins. We demonstrate that yeast Sgt1 adopts a unique binding mode, engaging primarily with the middle domain of Hsp90. Through simultaneous interaction with both Hsp90 and client proteins, Sgt1 enhances client maturation efficiency. Specifically, Sgt1 stabilizes Hsp90-client complexes and prevents their dissociation by the co-chaperone Aha1. Our findings reveal a previously unrecognized layer of Hsp90 regulation, highlighting Sgt1 as a critical modulator of chaperone cycle progression.
{"title":"The essential co-chaperone Sgt1 regulates client dwell time in the Hsp90 chaperone cycle","authors":"Sonja Engler, Florent Delhommel, Christopher Dodt, Abraham Lopez, Ofrah Faust, Annika Elimelech, Valeria Napolitano, Grzegorz M. Popowicz, Rina Rosenzweig, Michael Sattler, Johannes Buchner","doi":"10.1016/j.molcel.2025.12.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.12.002","url":null,"abstract":"The Hsp90 molecular chaperone system is regulated by numerous co-chaperones that modulate its function. In <em>Saccharomyces cerevisiae</em>, most of these cofactors can be deleted without affecting viability. Of the three essential ones, only the function of Sgt1 has remained enigmatic. Our <em>in vivo</em> and <em>in vitro</em> experiments define key structural elements and determine the essential function of Sgt1 in the chaperoning of client proteins. We demonstrate that yeast Sgt1 adopts a unique binding mode, engaging primarily with the middle domain of Hsp90. Through simultaneous interaction with both Hsp90 and client proteins, Sgt1 enhances client maturation efficiency. Specifically, Sgt1 stabilizes Hsp90-client complexes and prevents their dissociation by the co-chaperone Aha1. Our findings reveal a previously unrecognized layer of Hsp90 regulation, highlighting Sgt1 as a critical modulator of chaperone cycle progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"173 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813174","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.028
Rongrong Du, Michael J. Flynn, Karan Mahe, Monique Honsa, Bo Gu, Dongyang Li, Sean E. McGeary, Viviana Gradinaru, Ralf Jungmann, Michael B. Elowitz
Accurate control of transgene expression is important for research and therapy but is challenging to achieve in most settings. MicroRNA (miRNA)-based regulatory circuits can be incorporated within transgenes for improved control. However, the design principles, performance limits, and applications of these circuits in research and biotechnology have not been systematically determined. Here, combining modeling and experiments, we introduce miRNA-based circuit modules, termed “dosage invariant miRNA-mediated expression regulators” (DIMMERs), that establish precise, tunable control of transgene expression across diverse cell types to facilitate imaging, editing, and gene therapy. The circuits use multivalent miRNA regulatory interactions to achieve nearly uniform, tunable protein expression over two orders of magnitude variation in gene dosage. They function across diverse cell types and can be multiplexed for the independent regulation of multiple genes. DIMMERs reduce off-target CRISPR base editing, improve single-molecule imaging, and allow live tracking of adeno-associated virus (AAV)-delivered transgene expression in mouse cortical neurons. DIMMERs thus enable accurate regulation for research and biotechnology applications.
{"title":"miRNA modules for precise, tunable control of gene expression","authors":"Rongrong Du, Michael J. Flynn, Karan Mahe, Monique Honsa, Bo Gu, Dongyang Li, Sean E. McGeary, Viviana Gradinaru, Ralf Jungmann, Michael B. Elowitz","doi":"10.1016/j.molcel.2025.11.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.028","url":null,"abstract":"Accurate control of transgene expression is important for research and therapy but is challenging to achieve in most settings. MicroRNA (miRNA)-based regulatory circuits can be incorporated within transgenes for improved control. However, the design principles, performance limits, and applications of these circuits in research and biotechnology have not been systematically determined. Here, combining modeling and experiments, we introduce miRNA-based circuit modules, termed “dosage invariant miRNA-mediated expression regulators” (DIMMERs), that establish precise, tunable control of transgene expression across diverse cell types to facilitate imaging, editing, and gene therapy. The circuits use multivalent miRNA regulatory interactions to achieve nearly uniform, tunable protein expression over two orders of magnitude variation in gene dosage. They function across diverse cell types and can be multiplexed for the independent regulation of multiple genes. DIMMERs reduce off-target CRISPR base editing, improve single-molecule imaging, and allow live tracking of adeno-associated virus (AAV)-delivered transgene expression in mouse cortical neurons. DIMMERs thus enable accurate regulation for research and biotechnology applications.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"116 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777700","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.025
Catherine H. Freudenreich
{"title":"Time and space: How the circadian clock controls DNA break repair location and pathway choice","authors":"Catherine H. Freudenreich","doi":"10.1016/j.molcel.2025.11.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.025","url":null,"abstract":"","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"35 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784405","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.029
Ron Kelley, Sagar Khavnekar, Ricardo D. Righetto, Jessica Heebner, Martin Obr, Xianjun Zhang, Saikat Chakraborty, Grigory Tagiltsev, Alicia K. Michael, Sofie van Dorst, Florent Waltz, Caitlyn L. McCafferty, Lorenz Lamm, Simon Zufferey, Philippe Van der Stappen, Hugo van den Hoek, Wojciech Wietrzynski, Pavol Harar, William Wan, John A.G. Briggs, Abhay Kotecha
In situ cryo-electron tomography (cryo-ET) has emerged as the method of choice to investigate the structures of biomolecules in their native context. However, challenges remain for the efficient production and sharing of large-scale cryo-ET datasets. Here, we combined cryogenic plasma-based focused ion beam (cryo-PFIB) milling with recent advances in cryo-ET acquisition and processing to generate a dataset of 1,829 annotated tomograms of the green alga Chlamydomonas reinhardtii, which we provide as a community resource to drive method development and inspire biological discovery. To assay data quality, we performed subtomogram averaging of both soluble and membrane-bound complexes ranging in size from >3 MDa to ∼200 kDa, including 80S ribosomes, Rubisco, nucleosomes, microtubules, clathrin, photosystem II, and mitochondrial ATP synthase. The majority of these density maps reached sub-nanometer resolution, demonstrating the potential of this C. reinhardtii dataset as well as the promise of modern cryo-ET workflows and open data sharing to empower visual proteomics.
{"title":"Toward community-driven visual proteomics with large-scale cryo-electron tomography of Chlamydomonas reinhardtii","authors":"Ron Kelley, Sagar Khavnekar, Ricardo D. Righetto, Jessica Heebner, Martin Obr, Xianjun Zhang, Saikat Chakraborty, Grigory Tagiltsev, Alicia K. Michael, Sofie van Dorst, Florent Waltz, Caitlyn L. McCafferty, Lorenz Lamm, Simon Zufferey, Philippe Van der Stappen, Hugo van den Hoek, Wojciech Wietrzynski, Pavol Harar, William Wan, John A.G. Briggs, Abhay Kotecha","doi":"10.1016/j.molcel.2025.11.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.029","url":null,"abstract":"<em>In situ</em> cryo-electron tomography (cryo-ET) has emerged as the method of choice to investigate the structures of biomolecules in their native context. However, challenges remain for the efficient production and sharing of large-scale cryo-ET datasets. Here, we combined cryogenic plasma-based focused ion beam (cryo-PFIB) milling with recent advances in cryo-ET acquisition and processing to generate a dataset of 1,829 annotated tomograms of the green alga <em>Chlamydomonas reinhardtii</em>, which we provide as a community resource to drive method development and inspire biological discovery. To assay data quality, we performed subtomogram averaging of both soluble and membrane-bound complexes ranging in size from >3 MDa to ∼200 kDa, including 80S ribosomes, Rubisco, nucleosomes, microtubules, clathrin, photosystem II, and mitochondrial ATP synthase. The majority of these density maps reached sub-nanometer resolution, demonstrating the potential of this <em>C. reinhardtii</em> dataset as well as the promise of modern cryo-ET workflows and open data sharing to empower visual proteomics.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"31 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777701","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.026
Erdem M. Terzi, Richard Possemato
{"title":"Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis","authors":"Erdem M. Terzi, Richard Possemato","doi":"10.1016/j.molcel.2025.11.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.026","url":null,"abstract":"","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"10 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784784","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.030
Sandra Nitsch, Aria E. Coraor, Tamas Schauer, Yiheng Wu, Jianfeng Sun, Natalie Möritz, Jonas Funke, Harsh Nagpal, Gabriella N.L. Chua, Federica Battistini, Shannon M. Lauberth, Eva Richard, Modesto Orozco, Shixin Liu, Lourdes R. Desviat, Beat Fierz, Hendrik Dietz, Robert G. Roeder, Juan J. de Pablo, Robert Schneider
{"title":"H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations","authors":"Sandra Nitsch, Aria E. Coraor, Tamas Schauer, Yiheng Wu, Jianfeng Sun, Natalie Möritz, Jonas Funke, Harsh Nagpal, Gabriella N.L. Chua, Federica Battistini, Shannon M. Lauberth, Eva Richard, Modesto Orozco, Shixin Liu, Lourdes R. Desviat, Beat Fierz, Hendrik Dietz, Robert G. Roeder, Juan J. de Pablo, Robert Schneider","doi":"10.1016/j.molcel.2025.11.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.030","url":null,"abstract":"","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"114 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784785","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molcel.2025.11.020
Zeshi Li, Bhagyashree S. Joshi, Hongbo Yin, Ruud H. Wijdeven, Azen Koç, Dick W. Zijlmans, Irene Santos-Barriopedro, Hailiang Mei, Wei Wu, Milad Shademan, Filip M. Zawisza, Eric Bos, Pradeep Chopra, Marvin E. Tanenbaum, Thomas H. Sharp, Michiel Vermeulen, Vered Raz, Chirlmin Joo
{"title":"Cell-surface RNA forms ternary complex with RNA-binding proteins and heparan sulfate to recruit immune receptors","authors":"Zeshi Li, Bhagyashree S. Joshi, Hongbo Yin, Ruud H. Wijdeven, Azen Koç, Dick W. Zijlmans, Irene Santos-Barriopedro, Hailiang Mei, Wei Wu, Milad Shademan, Filip M. Zawisza, Eric Bos, Pradeep Chopra, Marvin E. Tanenbaum, Thomas H. Sharp, Michiel Vermeulen, Vered Raz, Chirlmin Joo","doi":"10.1016/j.molcel.2025.11.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.020","url":null,"abstract":"","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"29 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784781","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：