The lateral habenula (LHb) neurons and astrocytes have been strongly implicated in depression etiology, but it was not clear how the two dynamically interact during depression onset. Here, using multi-brain-region calcium photometry recording in freely moving mice, we discover that stress induces a most rapid astrocytic calcium rise and a bimodal neuronal response in the LHb. LHb astrocytic calcium requires the α1A-adrenergic receptor and depends on a recurrent neural network between the LHb and locus coeruleus (LC). Through the gliotransmitter glutamate and ATP/adenosine, LHb astrocytes mediate the second-wave LHb neuronal activation and norepinephrine (NE) release. Activation or inhibition of LHb astrocytic calcium signaling facilitates or prevents stress-induced depressive-like behaviors, respectively. These results identify a stress-induced positive feedback loop in the LHb-LC axis, with astrocytes being a critical signaling relay. The identification of this prominent neuron-glia interaction may shed light on stress management and depression prevention.
{"title":"Neuron-astrocyte coupling in lateral habenula mediates depressive-like behaviors","authors":"Qianqian Xin, Junying Wang, Jinkun Zheng, Yi Tan, Xiaoning Jia, Zheyi Ni, Zijie Xu, Jiesi Feng, Zhaofa Wu, Yulong Li, Xiao-Ming Li, Huan Ma, Hailan Hu","doi":"10.1016/j.cell.2025.04.010","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.010","url":null,"abstract":"The lateral habenula (LHb) neurons and astrocytes have been strongly implicated in depression etiology, but it was not clear how the two dynamically interact during depression onset. Here, using multi-brain-region calcium photometry recording in freely moving mice, we discover that stress induces a most rapid astrocytic calcium rise and a bimodal neuronal response in the LHb. LHb astrocytic calcium requires the α<sub>1A</sub>-adrenergic receptor and depends on a recurrent neural network between the LHb and locus coeruleus (LC). Through the gliotransmitter glutamate and ATP/adenosine, LHb astrocytes mediate the second-wave LHb neuronal activation and norepinephrine (NE) release. Activation or inhibition of LHb astrocytic calcium signaling facilitates or prevents stress-induced depressive-like behaviors, respectively. These results identify a stress-induced positive feedback loop in the LHb-LC axis, with astrocytes being a critical signaling relay. The identification of this prominent neuron-glia interaction may shed light on stress management and depression prevention.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"14 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866986","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}
Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H+ ATPase, proton efflux is mediated by a fast H+ leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate, two H+ equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H+ transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.
{"title":"SLC7A11 is an unconventional H+ transporter in lysosomes","authors":"Nan Zhou, Jingzhi Chen, Meiqin Hu, Na Wen, Weijie Cai, Ping Li, Liding Zhao, Yaping Meng, Dongdong Zhao, Xiaotong Yang, Siyu Liu, Fangqian Huang, Cheng Zhao, Xinghua Feng, Zikai Jiang, Enjun Xie, Hongxu Pan, Zhidong Cen, Xinhui Chen, Wei Luo, Haoxing Xu","doi":"10.1016/j.cell.2025.04.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.004","url":null,"abstract":"Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H<sup>+</sup> ATPase, proton efflux is mediated by a fast H<sup>+</sup> leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H<sup>+</sup> leak through downward flux of cystine and glutamate, two H<sup>+</sup> equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H<sup>+</sup> transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866988","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 : 2025-04-23DOI: 10.1016/j.cell.2025.04.001
Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel, Jens C. Brüning
Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.
{"title":"Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis","authors":"Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel, Jens C. Brüning","doi":"10.1016/j.cell.2025.04.001","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.001","url":null,"abstract":"Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (<em>Lepr</em>) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring <em>Lepr</em> expression in PNOC neurons on a <em>Lepr</em>-null obese background substantially reduces body weight. <em>Lepr</em> inactivation in PNOC neurons increases neuropeptide Y (<em>Npy</em>) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (<em>Agrp</em>). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOC<sup>ARC</sup> neurons, and overexpression of <em>Npy</em> in PNOC<sup>ARC</sup> neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPY<sup>ARC</sup> neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"17 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862382","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 : 2025-04-23DOI: 10.1016/j.cell.2025.03.046
Andrew B. Kleist, Martyna Szpakowska, Lindsay J. Talbot, Greg Slodkowicz, Duccio Malinverni, Monica A. Thomas, Kyler S. Crawford, Daniel J. McGrail, Acacia F. Dishman, Michael J. Wedemeyer, Madison Sluter, S. Stephen Yi, Nidhi Sahni, Francis C. Peterson, Andy Chevigné, Brian F. Volkman, M. Madan Babu
In humans, selective and promiscuous interactions between 46 secreted chemokine ligands and 23 cell surface chemokine receptors of the G-protein-coupled receptor (GPCR) family form a complex network to coordinate cell migration. While chemokines and their GPCRs each share common structural scaffolds, the molecular principles driving selectivity and promiscuity remain elusive. Here, we identify conserved, semi-conserved, and variable determinants (i.e., recognition elements) that are encoded and decoded by chemokines and their receptors to mediate interactions. Selectivity and promiscuity emerge from an ensemble of generalized (“public/conserved”) and specific (“private/variable”) determinants distributed among structured and unstructured protein regions, with ligands and receptors recognizing these determinants combinatorially. We employ these principles to engineer a viral chemokine with altered GPCR coupling preferences and provide a web resource to facilitate sequence-structure-function studies and protein design efforts for developing immuno-therapeutics and cell therapies.
在人体中，46 种分泌型趋化因子配体与 23 种 G 蛋白偶联受体（GPCR）家族的细胞表面趋化因子受体之间的选择性和杂合性相互作用形成了一个复杂的网络，以协调细胞迁移。虽然趋化因子及其 GPCR 都有共同的结构支架，但驱动选择性和杂交性的分子原理仍然难以捉摸。在这里，我们确定了由趋化因子及其受体编码和解码以介导相互作用的保守、半保守和可变决定因素（即识别元件）。选择性和杂交性产生于分布在结构化和非结构化蛋白质区域的通用（"公共/保守"）和特异（"私有/可变"）决定因子的组合，配体和受体组合识别这些决定因子。我们利用这些原理设计了一种具有改变的 GPCR 偶联偏好的病毒趋化因子，并提供了一种网络资源，以促进序列-结构-功能研究和蛋白质设计工作，从而开发免疫疗法和细胞疗法。
{"title":"Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network","authors":"Andrew B. Kleist, Martyna Szpakowska, Lindsay J. Talbot, Greg Slodkowicz, Duccio Malinverni, Monica A. Thomas, Kyler S. Crawford, Daniel J. McGrail, Acacia F. Dishman, Michael J. Wedemeyer, Madison Sluter, S. Stephen Yi, Nidhi Sahni, Francis C. Peterson, Andy Chevigné, Brian F. Volkman, M. Madan Babu","doi":"10.1016/j.cell.2025.03.046","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.046","url":null,"abstract":"In humans, selective and promiscuous interactions between 46 secreted chemokine ligands and 23 cell surface chemokine receptors of the G-protein-coupled receptor (GPCR) family form a complex network to coordinate cell migration. While chemokines and their GPCRs each share common structural scaffolds, the molecular principles driving selectivity and promiscuity remain elusive. Here, we identify conserved, semi-conserved, and variable determinants (i.e., recognition elements) that are encoded and decoded by chemokines and their receptors to mediate interactions. Selectivity and promiscuity emerge from an ensemble of generalized (“public/conserved”) and specific (“private/variable”) determinants distributed among structured and unstructured protein regions, with ligands and receptors recognizing these determinants combinatorially. We employ these principles to engineer a viral chemokine with altered GPCR coupling preferences and provide a web resource to facilitate sequence-structure-function studies and protein design efforts for developing immuno-therapeutics and cell therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"18 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862381","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 : 2025-04-23DOI: 10.1016/j.cell.2025.03.047
Won Jun Kim, Edie I. Crosse, Emma De Neef, Inaki Etxeberria, Erich Y. Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X. Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H. Winick, Alexander M. Lewis, Robert F. Stanley, Omar Abdel-Wahab
Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.
{"title":"Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias","authors":"Won Jun Kim, Edie I. Crosse, Emma De Neef, Inaki Etxeberria, Erich Y. Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X. Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H. Winick, Alexander M. Lewis, Robert F. Stanley, Omar Abdel-Wahab","doi":"10.1016/j.cell.2025.03.047","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.047","url":null,"abstract":"Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8<sup>+</sup> T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in <em>CLK3</em> and <em>RHOT2</em> resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"43 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862379","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 : 2025-04-23DOI: 10.1016/j.cell.2025.03.045
Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen, Sheng Zhong
Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH’s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.
{"title":"Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease","authors":"Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen, Sheng Zhong","doi":"10.1016/j.cell.2025.03.045","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.045","url":null,"abstract":"Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH’s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"4 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862380","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 : 2025-04-23DOI: 10.1016/j.cell.2025.03.044
Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A. Marti-Renom, Maria-Elena Torres-Padilla
The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.
{"title":"The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways","authors":"Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A. Marti-Renom, Maria-Elena Torres-Padilla","doi":"10.1016/j.cell.2025.03.044","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.044","url":null,"abstract":"The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"12 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862383","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 : 2025-04-22DOI: 10.1016/j.cell.2025.03.043
Susan Westfall, Maria E. Gentile, Tayla M. Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Röstel, Ryan D. Pardy, Giordano Mandato, Ghislaine Fontes, De’Broski Herbert, Heather J. Melichar, Valerie Abadie, Martin J. Richer, Donald C. Vinh, Joshua F.E. Koenig, Oliver J. Harrison, Maziar Divangahi, Sebastian Weis, Alex Gregorieff, Irah L. King
Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.
{"title":"A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection","authors":"Susan Westfall, Maria E. Gentile, Tayla M. Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Röstel, Ryan D. Pardy, Giordano Mandato, Ghislaine Fontes, De’Broski Herbert, Heather J. Melichar, Valerie Abadie, Martin J. Richer, Donald C. Vinh, Joshua F.E. Koenig, Oliver J. Harrison, Maziar Divangahi, Sebastian Weis, Alex Gregorieff, Irah L. King","doi":"10.1016/j.cell.2025.03.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.043","url":null,"abstract":"Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8<sup>+</sup> T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857792","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 : 2025-04-22DOI: 10.1016/j.cell.2025.03.033
Jingying Zhang, Bing Wang, Haoran Xu, Weidong Liu, Jingwei Yu, Qiuxia Wang, Hong Yu, Jin-Wei Wei, Rui Dai, Jinghang Zhou, Yuhang He, Di Zou, Jinhua Yang, Xinwei Ban, Qingliang Hu, Xiangbing Meng, Yong-Xin Liu, Binglei Wang, Bin Hu, Mingyu Wang, Yang Bai
Rice tillering is an important agronomic trait regulated by plant genetic and environmental factors. However, the role and mechanism of the root microbiota in modulating rice tillering have not been explored. Here, we examined the root microbiota composition and tiller numbers of 182 genome-sequenced rice varieties grown under field conditions and uncovered a significant correlation between root microbiota composition and rice tiller number. Using cultivated bacterial isolates, we demonstrated that various members of the root microbiota can regulate rice tillering in both laboratory and field conditions. Genetic, biochemical, and structural analyses revealed that cyclo(Leu-Pro), produced by the tiller-inhibiting bacterium Exiguobacterium R2567, activates the rice strigolactone (SL) signaling pathway by binding to the SL receptor OsD14, thus regulating tillering. The present work provides insight into how the root microbiota regulates key agronomic traits and offers a promising strategy for optimizing crop growth by harnessing the root microbiota in sustainable agriculture.
{"title":"Root microbiota regulates tiller number in rice","authors":"Jingying Zhang, Bing Wang, Haoran Xu, Weidong Liu, Jingwei Yu, Qiuxia Wang, Hong Yu, Jin-Wei Wei, Rui Dai, Jinghang Zhou, Yuhang He, Di Zou, Jinhua Yang, Xinwei Ban, Qingliang Hu, Xiangbing Meng, Yong-Xin Liu, Binglei Wang, Bin Hu, Mingyu Wang, Yang Bai","doi":"10.1016/j.cell.2025.03.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.033","url":null,"abstract":"Rice tillering is an important agronomic trait regulated by plant genetic and environmental factors. However, the role and mechanism of the root microbiota in modulating rice tillering have not been explored. Here, we examined the root microbiota composition and tiller numbers of 182 genome-sequenced rice varieties grown under field conditions and uncovered a significant correlation between root microbiota composition and rice tiller number. Using cultivated bacterial isolates, we demonstrated that various members of the root microbiota can regulate rice tillering in both laboratory and field conditions. Genetic, biochemical, and structural analyses revealed that cyclo(Leu-Pro), produced by the tiller-inhibiting bacterium <em>Exiguobacterium</em> R2567, activates the rice strigolactone (SL) signaling pathway by binding to the SL receptor OsD14, thus regulating tillering. The present work provides insight into how the root microbiota regulates key agronomic traits and offers a promising strategy for optimizing crop growth by harnessing the root microbiota in sustainable agriculture.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"12 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857791","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}
Epithelial tissues serve as the first line of host against bacterial infections. The self-organization of epithelial tissues continuously adapts to the architecture and mechanics of microenvironments, thereby dynamically impacting the initial niche of infections. However, the mechanism by which tissue geometry regulates bacterial infection remains poorly understood. Here, we showed geometry-guided infection patterns of bacteria in epithelial tissues using bioengineering strategies. We discovered that cellular traction forces play a crucial role in the regulation of bacterial invasive sites and marginal infection patterns in epithelial monolayers through triggering co-localization of mechanosensitive ion channel protein Piezo1 with bacteria. Further, we developed precise mechanobiology-based strategies to potentiate the antibacterial efficacy in animal models of wound and intestinal infection. Our findings demonstrate that tissue geometry exerts a key impact on mediating spatiotemporal infections of bacteria, which has important implications for the discovery and development of alternative strategies against bacterial infections.
{"title":"Tissue geometry spatiotemporally drives bacterial infections","authors":"Yiming Han, Xiaoye Liu, Shaoqi Qu, Xiaocen Duan, Yunqing Xiang, Nan Jiang, Shuyu Yang, Xu Fang, Liang Xu, Hui Wen, Yue Yu, Shuqiang Huang, Jianyong Huang, Kui Zhu","doi":"10.1016/j.cell.2025.03.042","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.042","url":null,"abstract":"Epithelial tissues serve as the first line of host against bacterial infections. The self-organization of epithelial tissues continuously adapts to the architecture and mechanics of microenvironments, thereby dynamically impacting the initial niche of infections. However, the mechanism by which tissue geometry regulates bacterial infection remains poorly understood. Here, we showed geometry-guided infection patterns of bacteria in epithelial tissues using bioengineering strategies. We discovered that cellular traction forces play a crucial role in the regulation of bacterial invasive sites and marginal infection patterns in epithelial monolayers through triggering co-localization of mechanosensitive ion channel protein Piezo1 with bacteria. Further, we developed precise mechanobiology-based strategies to potentiate the antibacterial efficacy in animal models of wound and intestinal infection. Our findings demonstrate that tissue geometry exerts a key impact on mediating spatiotemporal infections of bacteria, which has important implications for the discovery and development of alternative strategies against bacterial infections.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"125 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853170","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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