Pub Date : 2025-12-04DOI: 10.1016/j.cell.2025.11.014
Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad
Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
{"title":"A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis","authors":"Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad","doi":"10.1016/j.cell.2025.11.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.014","url":null,"abstract":"Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal <em>Gpx4</em> deletion or neuron-specific GPX4<sup>R152H</sup> expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673657","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 : 2025-12-04DOI: 10.1016/j.cell.2025.11.013
Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian
Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics in vivo. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin in vivo.
{"title":"Renal PIEZO2 is an essential regulator of renin","authors":"Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian","doi":"10.1016/j.cell.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.013","url":null,"abstract":"Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics <em>in vivo</em>. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin <em>in vivo</em>.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673658","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 : 2025-12-03DOI: 10.1016/j.cell.2025.11.006
Lisa K. Iwamoto-Stohl, Aleksandra A. Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A.T. Weatherbee, Antonia Weberling, Carlos W. Gantner, Rachel S. Mandelbaum, Richard J. Paulson, Lisa Lam, Tsui-Fen Chou, Magdalena Zernicka-Goetz
While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.
{"title":"Fertilization triggers early proteomic symmetry breaking in mammalian embryos","authors":"Lisa K. Iwamoto-Stohl, Aleksandra A. Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A.T. Weatherbee, Antonia Weberling, Carlos W. Gantner, Rachel S. Mandelbaum, Richard J. Paulson, Lisa Lam, Tsui-Fen Chou, Magdalena Zernicka-Goetz","doi":"10.1016/j.cell.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.006","url":null,"abstract":"While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657144","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 : 2025-12-03DOI: 10.1016/j.cell.2025.11.032
Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana
(Cell 187, 7637–7654.e1–e29; December 26, 2024)
（187,7637 - 7654.e1 - e29； 2024年12月26日）
{"title":"Retraction notice to: Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells","authors":"Wen-Wei Liang, Simon Müller, Sydney K. Hart, Hans-Hermann Wessels, Alejandro Méndez-Mancilla, Akash Sookdeo, Olivia Choi, Christina M. Caragine, Alba Corman, Lu Lu, Olena Kolumba, Breanna Williams, Neville E. Sanjana","doi":"10.1016/j.cell.2025.11.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.032","url":null,"abstract":"(Cell <em>187</em>, 7637–7654.e1–e29; December 26, 2024)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"117 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657142","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 : 2025-12-02DOI: 10.1016/j.cell.2025.11.007
Min Xie, Markus Eyting, Christian Bommer, Haroon Ahmed, Pascal Geldsetzer
Using natural experiments, we have previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.
{"title":"The effect of shingles vaccination at different stages of the dementia disease course","authors":"Min Xie, Markus Eyting, Christian Bommer, Haroon Ahmed, Pascal Geldsetzer","doi":"10.1016/j.cell.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.007","url":null,"abstract":"Using natural experiments, we have previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"158 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651425","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}
Heat stress triggers cell membrane lipid remodeling, yet whether this signals plants to perceive high temperatures and how such physical signals are decoded into biological signals remains unclear. Here, we demonstrate that diacylglycerol kinase 7 (DGK7) responds to heat stress at the plasma membrane, converting diacylglycerol into the second messenger, phosphatidic acid (PA). Subsequently, metal-dependent phosphodiesterase (MdPDE1) senses PA, acquires its activity by binding to PA, and translocates to the nucleus to degrade another second messenger, cyclic adenosine monophosphate (cAMP). MdPDE1 then elicits transcriptional landscape changes via altering cAMP signaling. Furthermore, G protein subunit thermotolerance 2 (TT2) inhibits DGK7 activity by Ser477 dephosphorylation, blocking MdPDE1 activity and nuclear translocation. Notably, field trials demonstrated the promising applications of this mechanism that confers varying degrees of rice thermotolerance as needed. This study establishes a complete hierarchical thermo-decoding mechanism that opens opportunities for creating customized heat-tolerant crops, aiding in mitigating yield losses from global warming.
{"title":"A stepwise decoding mechanism for heat sensing in plants connects lipid remodeling to a nuclear signaling cascade","authors":"Yi Kan, Xiao-Rui Mu, Fangfang Qu, Zhi-An Dai, Jin Gao, Ning-Jing Liu, Siqi Li, Jun-Xiang Shan, Wang-Wei Ye, Nai-Qian Dong, Xiaolan Huang, Yi-Bing Yang, Shuang-Qin Guo, Jie-Jie Lei, Ying-Jie Cao, Ji-Fu Zhou, Pengcheng Li, Jianchuan Wang, Yixue Li, Hong-Xuan Lin, Youshun Lin","doi":"10.1016/j.cell.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.003","url":null,"abstract":"Heat stress triggers cell membrane lipid remodeling, yet whether this signals plants to perceive high temperatures and how such physical signals are decoded into biological signals remains unclear. Here, we demonstrate that diacylglycerol kinase 7 (DGK7) responds to heat stress at the plasma membrane, converting diacylglycerol into the second messenger, phosphatidic acid (PA). Subsequently, metal-dependent phosphodiesterase (MdPDE1) senses PA, acquires its activity by binding to PA, and translocates to the nucleus to degrade another second messenger, cyclic adenosine monophosphate (cAMP). MdPDE1 then elicits transcriptional landscape changes via altering cAMP signaling. Furthermore, G protein subunit thermotolerance 2 (TT2) inhibits DGK7 activity by Ser<sup>477</sup> dephosphorylation, blocking MdPDE1 activity and nuclear translocation. Notably, field trials demonstrated the promising applications of this mechanism that confers varying degrees of rice thermotolerance as needed. This study establishes a complete hierarchical thermo-decoding mechanism that opens opportunities for creating customized heat-tolerant crops, aiding in mitigating yield losses from global warming.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657146","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 : 2025-12-02DOI: 10.1016/j.cell.2025.11.005
Yuzhe Shi, Michael A. Lopez, Ivan S. Kotchetkov, Nayan Jain, Zeguo Zhao, Leena Halim, Anton Dobrin, Karlo Perica, Sophie A. Hanina, Vinagolu K. Rajasekhar, Michael G. Kharas, Michel Sadelain
Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.
{"title":"pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication","authors":"Yuzhe Shi, Michael A. Lopez, Ivan S. Kotchetkov, Nayan Jain, Zeguo Zhao, Leena Halim, Anton Dobrin, Karlo Perica, Sophie A. Hanina, Vinagolu K. Rajasekhar, Michael G. Kharas, Michel Sadelain","doi":"10.1016/j.cell.2025.11.005","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.005","url":null,"abstract":"Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 1A domain imparted greater expansion, cytokine production, and <em>in vivo</em> persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"73 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651404","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 : 2025-12-02DOI: 10.1016/j.cell.2025.11.004
Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G. Abreu, Leander Ammar, Anjali R. Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W. Kirschner, Markus Basan
Mechanical forces influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We demonstrate that membrane potential is an important mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which, in turn, alters membrane potential. Membrane potential then regulates cell number density in epithelia by controlling cell growth, proliferation, and cell elimination. Mechanistically, we show that changes in membrane potential control signaling through the Hippo and mitogen-activated protein kinase (MAPK) pathways and potentially other signaling pathways that originate at the cell membrane. While many molecular interactions are known to affect Hippo signaling, the upstream signal that activates the canonical Hippo pathway at the membrane has previously been elusive. Our results establish membrane potential as an important regulator of growth and tissue homeostasis.
{"title":"Membrane potential mediates the cellular response to mechanical pressure","authors":"Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G. Abreu, Leander Ammar, Anjali R. Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W. Kirschner, Markus Basan","doi":"10.1016/j.cell.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.004","url":null,"abstract":"Mechanical forces influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We demonstrate that membrane potential is an important mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which, in turn, alters membrane potential. Membrane potential then regulates cell number density in epithelia by controlling cell growth, proliferation, and cell elimination. Mechanistically, we show that changes in membrane potential control signaling through the Hippo and mitogen-activated protein kinase (MAPK) pathways and potentially other signaling pathways that originate at the cell membrane. While many molecular interactions are known to affect Hippo signaling, the upstream signal that activates the canonical Hippo pathway at the membrane has previously been elusive. Our results establish membrane potential as an important regulator of growth and tissue homeostasis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651427","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 : 2025-12-02DOI: 10.1016/j.cell.2025.10.044
Qinqin Zhao, Jiri Vlach, Young-Jun Park, Yongjun Tan, Savannah K. Bertolli, Pooja Srinivas, Pinyu Liao, Connor R. Fitzpatrick, Jeffery L. Dangl, Parastoo Azadi, Frank DiMaio, S. Brook Peterson, Dapeng Zhang, David Veesler, Joseph D. Mougous
Bacteria exist in competitive and rapidly changing environments in which the nature of future threats cannot be easily predicted. Streptomyces coelicolor produces three antibacterial umbrella particles that harbor distinct polymorphic toxin domains and an overlapping set of six diversified lectins. Here, we show that the exquisite specificity of umbrella particles derives from lectin-mediated species-specific binding to previously undescribed hypervariable surface glycoconjugates. A cryo-electron microscopy (cryo-EM) structure of one such lectin in complex with its oligosaccharide substrate defines the molecular basis for targeting through the coordinated recognition of multiple glycan features. Biochemical and genetic studies of several target species, in conjunction with lectin-swapping experiments, support a model whereby S. coelicolor umbrella toxin diversification at the levels of lectin composition and toxin polymorphism represents a unique, two-tiered bet-hedging strategy. Bioinformatic analyses support this as a means by which the unusual architecture of umbrella toxins offers Streptomyces a generalizable strategy to antagonize an unpredictable array of competitors.
{"title":"The unique architecture of umbrella toxins permits a two-tiered molecular bet-hedging strategy for interbacterial antagonism","authors":"Qinqin Zhao, Jiri Vlach, Young-Jun Park, Yongjun Tan, Savannah K. Bertolli, Pooja Srinivas, Pinyu Liao, Connor R. Fitzpatrick, Jeffery L. Dangl, Parastoo Azadi, Frank DiMaio, S. Brook Peterson, Dapeng Zhang, David Veesler, Joseph D. Mougous","doi":"10.1016/j.cell.2025.10.044","DOIUrl":"https://doi.org/10.1016/j.cell.2025.10.044","url":null,"abstract":"Bacteria exist in competitive and rapidly changing environments in which the nature of future threats cannot be easily predicted. <em>Streptomyces coelicolor</em> produces three antibacterial umbrella particles that harbor distinct polymorphic toxin domains and an overlapping set of six diversified lectins. Here, we show that the exquisite specificity of umbrella particles derives from lectin-mediated species-specific binding to previously undescribed hypervariable surface glycoconjugates. A cryo-electron microscopy (cryo-EM) structure of one such lectin in complex with its oligosaccharide substrate defines the molecular basis for targeting through the coordinated recognition of multiple glycan features. Biochemical and genetic studies of several target species, in conjunction with lectin-swapping experiments, support a model whereby <em>S. coelicolor</em> umbrella toxin diversification at the levels of lectin composition and toxin polymorphism represents a unique, two-tiered bet-hedging strategy. Bioinformatic analyses support this as a means by which the unusual architecture of umbrella toxins offers <em>Streptomyces</em> a generalizable strategy to antagonize an unpredictable array of competitors.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"72 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657148","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 : 2025-12-01DOI: 10.1016/j.cell.2025.10.036
Fernando Medina Ferrer, Dipti D. Nayak
Archaeal transcription is a hybrid of eukaryotic and prokaryotic features: an RNA polymerase II (RNAPII)-like polymerase transcribes genes organized in circular chromosomes within cells devoid of a nucleus. Consequently, archaeal genomes are depleted of transcriptional regulators found in other domains of life. Here, we outline the discovery of a cryptic, archaea-specific family of ligand-binding regulatory transcription factors (TFs), called AmzR (archaeal metabolite-sensing zipper-like regulators). We identify AmzR using an evolution-based genetic screen and show that it is a repressor of methanogenic growth on methylamines in the archaeon Methanosarcina acetivorans. AmzR binds its target promoters as an oligomer using paired basic α-helices akin to eukaryotic leucine zippers. AmzR also binds methylamines, which reduces its DNA-binding affinity and allows it to function as a one-component system commonly found in prokaryotes, while containing a eukaryotic-like DNA-binding motif. The AmzR family of TFs are widespread in archaea and broaden the scope of innovations at the prokaryote-eukaryote interface.
{"title":"An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms","authors":"Fernando Medina Ferrer, Dipti D. Nayak","doi":"10.1016/j.cell.2025.10.036","DOIUrl":"https://doi.org/10.1016/j.cell.2025.10.036","url":null,"abstract":"Archaeal transcription is a hybrid of eukaryotic and prokaryotic features: an RNA polymerase II (RNAPII)-like polymerase transcribes genes organized in circular chromosomes within cells devoid of a nucleus. Consequently, archaeal genomes are depleted of transcriptional regulators found in other domains of life. Here, we outline the discovery of a cryptic, archaea-specific family of ligand-binding regulatory transcription factors (TFs), called AmzR (archaeal metabolite-sensing zipper-like regulators). We identify AmzR using an evolution-based genetic screen and show that it is a repressor of methanogenic growth on methylamines in the archaeon <em>Methanosarcina acetivorans</em>. AmzR binds its target promoters as an oligomer using paired basic α-helices akin to eukaryotic leucine zippers. AmzR also binds methylamines, which reduces its DNA-binding affinity and allows it to function as a one-component system commonly found in prokaryotes, while containing a eukaryotic-like DNA-binding motif. The AmzR family of TFs are widespread in archaea and broaden the scope of innovations at the prokaryote-eukaryote interface.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"108 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651424","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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