Cell reportsPub Date : 2025-03-25Epub Date: 2025-03-12DOI: 10.1016/j.celrep.2025.115399
Yuyu Jiang, Yunkai Zhang, Xiaohui Wang, Yan Xiang, Zeting Wang, Bo Wang, Yingying Ding, Ying Gao, Bing Rui, Jie Bai, Yue Ding, Chang Chen, Zhenzhen Zhan, Xingguang Liu
{"title":"Phosphatase PHLPP1 is an alveolar-macrophage-intrinsic transcriptional checkpoint controlling pulmonary fibrosis.","authors":"Yuyu Jiang, Yunkai Zhang, Xiaohui Wang, Yan Xiang, Zeting Wang, Bo Wang, Yingying Ding, Ying Gao, Bing Rui, Jie Bai, Yue Ding, Chang Chen, Zhenzhen Zhan, Xingguang Liu","doi":"10.1016/j.celrep.2025.115399","DOIUrl":"10.1016/j.celrep.2025.115399","url":null,"abstract":"<p><p>Alveolar macrophages (AMs) are crucial for lung homeostasis, and their dysfunction causes uncontrolled fibrotic responses and pulmonary disorders. Protein phosphatases control multiple cellular events. However, whether nuclear phosphatases cooperate with histone modifiers to affect pulmonary fibrosis progress remains obscure. Here, we identified pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) as a key protective factor for pulmonary fibrosis. Transcriptomics and epigenomics data confirmed that PHLPP1 selectively targeted Kruppel-like factor 4 (KLF4) for transcriptional inhibition in AMs. Nuclear PHLPP1 directly bound and dephosphorylated histone deacetylase 8 (HDAC8) at serine 39, thereby enhancing its deacetylase enzyme activity and subsequently suppressing KLF4 expression via the decreased histone acetylation and chromatin accessibility. Thus, loss of PHLPP1 amplified KLF4-centric profibrotic transcriptional program in AMs, while intratracheal administration of Klf4-short hairpin RNA (shRNA) adeno-associated virus ameliorated lung fibrosis in PHLPP1-deficient mice. Our study implies that targeting decreased PHLPP1 in AMs might be a promising therapeutic strategy for pulmonary fibrosis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115399"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630211","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}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-03-17DOI: 10.1016/j.celrep.2025.115436
Nitsan Albocher-Kedem, Meta Heidenreich, Amir Fadel, Elizabeta Sirotkin, Omer Goldberger, Anat Nussbaum-Shochat, Emmanuel D Levy, Ora Schueler-Furman, Maya Schuldiner, Orna Amster-Choder
{"title":"Uncovering the mechanism for polar sequestration of the major bacterial sugar regulator by high-throughput screens and 3D interaction modeling.","authors":"Nitsan Albocher-Kedem, Meta Heidenreich, Amir Fadel, Elizabeta Sirotkin, Omer Goldberger, Anat Nussbaum-Shochat, Emmanuel D Levy, Ora Schueler-Furman, Maya Schuldiner, Orna Amster-Choder","doi":"10.1016/j.celrep.2025.115436","DOIUrl":"10.1016/j.celrep.2025.115436","url":null,"abstract":"<p><p>The poles of rod-shaped bacteria emerge as regulatory hubs. We have shown that enzyme I (EI), the major bacterial sugar metabolism regulator, is sequestered when not needed in TmaR phase-separated condensates in Escherichia coli cell poles. Here, we combined genetic and automated microscopy screens to identify residues in EI and TmaR that are important for their interaction and colocalization. Mutating these residues affects EI-TmaR interaction in bacteria and impairs co-phase separation in yeast. The results were used to generate an EI-TmaR interaction model, which agrees with coevolution data and is supported by conservation of the interacting residues and EI-TmaR colocalization in other species. Mutating residues predicted to interact electrostatically further supports our model. The model explains how TmaR controls EI activity and its interaction with the phosphoprotein HPr and, hence, sugar uptake. Our study highlights the importance of sugar metabolism spatial regulation during evolution and presents a way to unravel protein-protein interactions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115436"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-02-19DOI: 10.1016/j.celrep.2025.115337
Zhangsong Wu, Chen Qiu, Yiming Liu, Xiaoyi Yan, Qiaohui Li, Shirui Jiang, Jun Xu, Xin Pan, Fang Ye, Zhiyi Zhang, Peiruo Ning, Binghao Zhang, Lezhi Xu, Bangning Cheng, Xufu Xiang, Chungen Qian, Yang Du, Geng Chen
{"title":"Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity.","authors":"Zhangsong Wu, Chen Qiu, Yiming Liu, Xiaoyi Yan, Qiaohui Li, Shirui Jiang, Jun Xu, Xin Pan, Fang Ye, Zhiyi Zhang, Peiruo Ning, Binghao Zhang, Lezhi Xu, Bangning Cheng, Xufu Xiang, Chungen Qian, Yang Du, Geng Chen","doi":"10.1016/j.celrep.2025.115337","DOIUrl":"10.1016/j.celrep.2025.115337","url":null,"abstract":"<p><p>Prolactin-releasing peptide receptor (PrRPR), a notable member of the class A peptide-GPCR (G-protein-coupled receptor) family, regulates diverse physiology functions upon activation by PrRP. Herein, we reveal that PrRPR could engage with not only the G<sub>q/11</sub> pathway but also the G<sub>i/o</sub> pathway. We further resolve the structures of the PrRPR-G<sub>q</sub> and PrRPR-G<sub>i</sub> complexes using cryoelectron microscopy (cryo-EM), with PrRP31 as the endogenous ligand. These high-resolution structures enhance our understanding of PrRPR-ligand interactions, aiding the development of targeted drugs aiming at this crucial peptide-receptor system. Comparing these structures with counterparts of other RF-amide peptide receptors accentuates the crucial function of the RF-amide motif in activating receptors and sheds light on the universal mechanism for RF-amide motif detection by RF-amide receptors. Furthermore, structural and functional analysis indicates that conformational alterations in the intracellular loops (ICLs), along with the \"wavy hook\" of Gα, may explain the selective coupling of G proteins in PrRPR signaling.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115337"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467213","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}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-03-08DOI: 10.1016/j.celrep.2025.115390
Dong Qian, Muxuan Wang, Yue Niu, Yang Yang, Yun Xiang
{"title":"Sexual reproduction in plants under high temperature and drought stress.","authors":"Dong Qian, Muxuan Wang, Yue Niu, Yang Yang, Yun Xiang","doi":"10.1016/j.celrep.2025.115390","DOIUrl":"10.1016/j.celrep.2025.115390","url":null,"abstract":"<p><p>Climate-change-induced extreme heat and drought increasingly threaten plant growth and development, with a particularly significant impact on sexual reproduction. Heat and drought stress can disrupt key stages of plant sexual reproduction, including flowering time, gametophyte development, pollination, and seed formation, leading to infertility and substantial yield reductions in crops. This review systematically summarizes the latest research on the effects of heat and drought stress on various stages of plant sexual reproduction and proposes specific strategies to mitigate the agricultural hazards posed by these stresses. By providing an in-depth analysis of the underlying mechanisms and regulatory networks, this review offers a theoretical basis for advancing fundamental research and optimizing agricultural practices to address the severe challenges climate change presents to agriculture.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115390"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decoding the ontogeny of myeloid lineage diversity by cross-species and developmental analyses of hematopoietic progenitor atlases.","authors":"Sheng Pan, Haoyu Tang, Bingpeng Yao, Guoxiong Tian, Beibei Sun, Yangmingzi Hu, Yan Chen, Jiaqian Li, Xiao Xu, Chao Zhang, Songmin Ying","doi":"10.1016/j.celrep.2025.115406","DOIUrl":"10.1016/j.celrep.2025.115406","url":null,"abstract":"<p><p>Myeloid cells play vital roles in homeostasis and immune responses in vertebrates, but the developmental pathway underlying their lineage diversity remains elusive. Here, we construct a single-cell transcriptional map of myeloid progenitors from mouse bone marrow and conduct cross-species and developmental analyses across human, monkey, mouse, and zebrafish. We uncover a conserved specification program separating the eosinophil-basophil-mast cell (EBM) lineage and neutrophil-monocyte (NM) lineage, reclassifying myeloid cells beyond the conventional granulocytic and monocytic framework. By generating Ikzf2-EGFP reporter mice, we identify IKZF2 as a priming marker for EBM lineage specification. Ikzf2-EGFP<sup>+</sup> and Ikzf2-EGFP<sup>-</sup> granulocyte-monocyte progenitors (GMPs) exhibit distinct potential to generate EBM and NM lineages, and Ikzf2-EGFP expression robustly distinguishes their progenies. Additionally, we demonstrate that lineage specification emerges early during myelopoiesis. These findings provide a redefined perspective on myeloid lineage ontogeny, highlighting the conservation of lineage specification and offering insights into the understanding and therapeutic development of myelopoiesis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115406"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PIEZO1-dependent mode switch of neuronal migration in heterogeneous microenvironments in the developing brain.","authors":"Naotaka Nakazawa, Gianluca Grenci, Yoshitaka Kameo, Noriko Takeda, Tsuyoshi Sawada, Junko Kurisu, Zhejing Zhang, Kenichi Toma, Taiji Adachi, Keiko Nonomura, Mineko Kengaku","doi":"10.1016/j.celrep.2025.115405","DOIUrl":"10.1016/j.celrep.2025.115405","url":null,"abstract":"<p><p>The migration of newborn neurons is essential for brain morphogenesis and circuit formation, yet controversy exists regarding how neurons generate the driving force against strong mechanical stresses in crowded neural tissues. We found that cerebellar granule neurons employ a mechanosensing mechanism to switch the driving forces to maneuver in irregular brain tissue. In two-dimensional (2D) cultures, actomyosin is enriched in the leading process, exerting traction force on the cell soma. In tissue or 3D confinement, however, actomyosin concentrates at the posterior cell membrane, generating contractile forces that assist passage through narrow spaces, working alongside the traction force in the leading process. The 3D migration is initiated by the activation of a mechanosensitive channel, PIEZO1. PIEZO1-induced calcium influx in the soma triggers the PKC-ezrin cascade, which recruits actomyosin and transmits its contractile force to the posterior plasma membrane. Thus, migrating neurons adapt their motility modes in distinct extracellular environments in the developing brain.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115405"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575697","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}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-03-10DOI: 10.1016/j.celrep.2025.115407
Anna Gabele, Maximilian Sprang, Mert Cihan, Mareen Welzel, Assel Nurbekova, Karolina Romaniuk, Sarah Dietzen, Matthias Klein, Georg Bündgen, Maxim Emelianov, Gregory Harms, Krishnaraj Rajalingam, Tanja Ziesmann, Katrin Pape, Beatrice Wasser, David Gomez-Zepeda, Kathrin Braband, Michael Delacher, Niels Lemmermann, Stefan Bittner, Miguel A Andrade-Navarro, Stefan Tenzer, Katja Luck, Tobias Bopp, Ute Distler
{"title":"Unveiling IRF4-steered regulation of context-dependent effector programs in CD4<sup>+</sup> T cells under Th17- and Treg-skewing conditions.","authors":"Anna Gabele, Maximilian Sprang, Mert Cihan, Mareen Welzel, Assel Nurbekova, Karolina Romaniuk, Sarah Dietzen, Matthias Klein, Georg Bündgen, Maxim Emelianov, Gregory Harms, Krishnaraj Rajalingam, Tanja Ziesmann, Katrin Pape, Beatrice Wasser, David Gomez-Zepeda, Kathrin Braband, Michael Delacher, Niels Lemmermann, Stefan Bittner, Miguel A Andrade-Navarro, Stefan Tenzer, Katja Luck, Tobias Bopp, Ute Distler","doi":"10.1016/j.celrep.2025.115407","DOIUrl":"10.1016/j.celrep.2025.115407","url":null,"abstract":"<p><p>The transcription factor interferon regulatory factor 4 (IRF4) is crucial for the fate determination of pro-inflammatory T helper (Th) 17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, the molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. Here, we integrated data derived from affinity-purification and full mass-spectrometry-based proteome analysis with chromatin immunoprecipitation sequencing. This allowed the characterization of subtype-specific molecular programs and the identification of IRF4 interactors in the Th17/Treg context. Our data reveal that IRF4-interacting transcription factors are recruited to IRF composite elements for the regulation of cell-type-specific transcriptional programs as exemplarily demonstrated for FLI1, which, in cooperation with IRF4, promotes Th17-specific gene expression. FLI1 inhibition markedly impaired Th17 differentiation. The present \"omics\" dataset provides a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115407"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604255","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}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-03-18DOI: 10.1016/j.celrep.2025.115497
Michelle Lee Lynskey, Emily E Brown, Ragini Bhargava, Anne R Wondisford, Jean-Baptiste Ouriou, Oliver Freund, Ray W Bowman, Baylee A Smith, Santana M Lardo, Sandra Schamus-Hayes, Sarah J Hainer, Roderick J O'Sullivan
{"title":"HIRA protects telomeres against R-loop-induced instability in ALT cancer cells.","authors":"Michelle Lee Lynskey, Emily E Brown, Ragini Bhargava, Anne R Wondisford, Jean-Baptiste Ouriou, Oliver Freund, Ray W Bowman, Baylee A Smith, Santana M Lardo, Sandra Schamus-Hayes, Sarah J Hainer, Roderick J O'Sullivan","doi":"10.1016/j.celrep.2025.115497","DOIUrl":"10.1016/j.celrep.2025.115497","url":null,"abstract":"","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115497"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662499","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}
Cell reportsPub Date : 2025-03-25Epub Date: 2025-02-20DOI: 10.1016/j.celrep.2025.115311
Stephanie A Barnes, Aurore Thomazeau, Peter S B Finnie, Maxwell J Heinrich, Arnold J Heynen, Noburu H Komiyama, Seth G N Grant, Frank S Menniti, Emily K Osterweil, Mark F Bear
{"title":"Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes.","authors":"Stephanie A Barnes, Aurore Thomazeau, Peter S B Finnie, Maxwell J Heinrich, Arnold J Heynen, Noburu H Komiyama, Seth G N Grant, Frank S Menniti, Emily K Osterweil, Mark F Bear","doi":"10.1016/j.celrep.2025.115311","DOIUrl":"10.1016/j.celrep.2025.115311","url":null,"abstract":"<p><p>N-methyl-D-aspartate (NMDA)-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis. Using subtype-selective pharmacological and genetic tools, we find that structural plasticity is dependent on ligand binding to GluN2B-containing NMDA receptors (NMDARs) and signaling via the GluN2B carboxy-terminal domain (CTD). Disruption of non-ionotropic signaling by replacing the GluN2B CTD with the GluN2A CTD leads to an increase in spine density, dysregulated basal protein synthesis, exaggerated long-term depression mediated by G-protein-coupled metabotropic glutamate receptors (mGluR-LTD), and epileptiform activity reminiscent of phenotypes observed in the Fmr1 knockout (KO) model of fragile X syndrome. By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":" ","pages":"115311"},"PeriodicalIF":7.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472313","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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