Science Signaling最新文献

{"title":"Extracellular proximal interaction profiling by cell surface–targeted TurboID reveals LDLR as a partner of liganded EGFR","authors":"Rasha Al Mismar,&nbsp;Payman Samavarchi-Tehrani,&nbsp;Brendon Seale,&nbsp;Vesal Kasmaeifar,&nbsp;Claire E. Martin,&nbsp;Anne-Claude Gingras","doi":"10.1126/scisignal.adl6164","DOIUrl":"10.1126/scisignal.adl6164","url":null,"abstract":"<div >Plasma membrane proteins play pivotal roles in receiving and transducing signals from other cells and from the environment and are vital for cellular functionality. Enzyme-based, proximity-dependent approaches, such as biotin identification (BioID), combined with mass spectrometry have begun to illuminate the landscape of proximal protein interactions within intracellular compartments. To extend the potential of these approaches to study the extracellular environment, we developed extracellular TurboID (ecTurboID), a method designed to profile the interactions between proteins on the surfaces of living cells over short timescales using the fast-acting biotin ligase TurboID. After optimizing our experimental and data analysis strategies to capture extracellular proximity interactions, we used ecTurboID to reveal the proximal interactomes of several plasma membrane proteins, including the epidermal growth factor receptor (EGFR). We found that EGF stimulation induced an association between EGFR and the low-density lipoprotein receptor (LDLR) and changed the interactome of LDLR by increasing its proximity with proteins that regulate EGFR signaling. The identification of this interaction between two well-studied and clinically relevant receptors illustrates the utility of our modified proximity labeling methodology for identifying dynamic extracellular associations between plasma membrane proteins.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 861","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584683","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":"The cancer risk of repeat RNAs","authors":"Wei Wong","doi":"10.1126/scisignal.adu2651","DOIUrl":"10.1126/scisignal.adu2651","url":null,"abstract":"<div >Repeat RNAs reprogram tumor cells and cancer-associated fibroblasts in pancreatic cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 861","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584688","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":"The de novo purine synthesis enzyme Adssl1 promotes cardiomyocyte proliferation and cardiac regeneration","authors":"Zhigang Li,&nbsp;Xiaxi Dong,&nbsp;Lingfang Zhuang,&nbsp;Kangni Jia,&nbsp;Haomai Cheng,&nbsp;Hang Sun,&nbsp;Yuke Cui,&nbsp;Wenqi Ma,&nbsp;Keying Wei,&nbsp;Pupu Zhang,&nbsp;Hongyang Xie,&nbsp;Lei Yi,&nbsp;Zhiyong Chen,&nbsp;Lin Lu,&nbsp;Tao Li,&nbsp;Ruiyan Zhang,&nbsp;Xiaoxiang Yan","doi":"10.1126/scisignal.adn3285","DOIUrl":"10.1126/scisignal.adn3285","url":null,"abstract":"<div >There is a short window during which the neonatal heart has the proliferative capacity to completely repair damage, an ability that is lost in adulthood. Inducing proliferation in adult cardiomyocytes by reactivating cell cycle reentry after myocardial infarction (MI) improves cardiac function. De novo purine synthesis is a critical source of nucleotides for cell proliferation. Here, using loss- and gain-of-function genetic approaches, we explored the role of the muscle-specific de novo purine synthesis enzyme Adssl1 in cardiac regeneration. Deletion of Adssl1 in mouse neonatal hearts reduced cardiomyocyte proliferation and attenuated heart regeneration after apical resection. Conversely, cardiomyocyte-specific Adssl1 overexpression extended the postnatal regenerative window and induced robust cell cycle reentry after MI, which decreased fibrotic scar size and improved cardiac function. RNA sequencing analysis suggested that Adssl1 overexpression induced strong dedifferentiation and cell cycle entry. Moreover, LC-MS/MS analysis showed that Adssl1 overexpression was associated with increased amounts of purine metabolites, including inosine, which is in clinical use. Administration of exogenous inosine promoted cardiac repair after MI in adult mice. At a molecular level, the increase in purine metabolite production mediated by Adssl1 enhanced the activity of the proliferation-promoting mTORC1 pathway. Our study identifies a role for Adssl1 in supporting cardiomyocyte proliferation and cardiac regeneration.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541119","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":"Neurons go antiviral","authors":"Amy E. Baek","doi":"10.1126/scisignal.adu1029","DOIUrl":"10.1126/scisignal.adu1029","url":null,"abstract":"<div >A neuropeptide-receptor pair promotes the differentiation of T_H1 cells and enhances their response to viral infection.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541120","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":"CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism","authors":"Vincent Rondeau,&nbsp;Maria Kalogeraki,&nbsp;Lilian Roland,&nbsp;Zeina Abou Nader,&nbsp;Vanessa Gourhand,&nbsp;Amélie Bonaud,&nbsp;Julia Lemos,&nbsp;Mélanie Khamyath,&nbsp;Clémentine Moulin,&nbsp;Bérénice Schell,&nbsp;Marc Delord,&nbsp;Ghislain Bidaut,&nbsp;Séverine Lecourt,&nbsp;Christelle Freitas,&nbsp;Adrienne Anginot,&nbsp;Nathalie Mazure,&nbsp;David H. McDermott,&nbsp;Véronique Parietti,&nbsp;Niclas Setterblad,&nbsp;Nicolas Dulphy,&nbsp;Françoise Bachelerie,&nbsp;Michel Aurrand-Lions,&nbsp;Daniel Stockholm,&nbsp;Camille Lobry,&nbsp;Philip M. Murphy,&nbsp;Marion Espéli,&nbsp;Stéphane J. C. Mancini,&nbsp;Karl Balabanian","doi":"10.1126/scisignal.adl5100","DOIUrl":"10.1126/scisignal.adl5100","url":null,"abstract":"<div >Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated <i>CXCR4</i> mutation (<i>CXCR4¹⁰¹³</i>) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in <i>CXCR4¹⁰¹³</i> knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in <i>CXCR4¹⁰¹³</i> knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541122","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":"Mechanosensing by Piezo1 in gastric ghrelin cells contributes to hepatic lipid homeostasis in mice","authors":"Jinshan Zhang,&nbsp;Yawen Zhao,&nbsp;Shaohong Wu,&nbsp;Mengxue Han,&nbsp;Luyang Gao,&nbsp;Ke Yang,&nbsp;Hui Chen,&nbsp;Cunchuan Wang,&nbsp;Geyang Xu","doi":"10.1126/scisignal.adq9463","DOIUrl":"10.1126/scisignal.adq9463","url":null,"abstract":"<div >Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of <i>Piezo1</i> (<i>Ghrl-Piezo1^−/−</i>) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in <i>Ghrl-Piezo1^−/−</i> mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in <i>Ghrl-Piezo1^−/−</i> mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 859","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adq9463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511662","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}

{"title":"Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells","authors":"Teresa Rosenlehner,&nbsp;Stefanie Pennavaria,&nbsp;Batuhan Akçabozan,&nbsp;Shiva Jahani,&nbsp;Thomas J. O''Neill,&nbsp;Daniel Krappmann,&nbsp;Tobias Straub,&nbsp;Jan Kranich,&nbsp;Reinhard Obst","doi":"10.1126/scisignal.adi8753","DOIUrl":"10.1126/scisignal.adi8753","url":null,"abstract":"<div >Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 859","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511664","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":"Nuclear pore decoys fool viruses","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.adt8958","DOIUrl":"10.1126/scisignal.adt8958","url":null,"abstract":"<div >Cytoplasmic condensates that mimic nuclear pore complexes entice viruses away from the nucleus.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 859","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511663","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":"The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters","authors":"Alba de Juan,&nbsp;Darawan Tabtim-On,&nbsp;Alice Coillard,&nbsp;Burkhard Becher,&nbsp;Christel Goudot,&nbsp;Elodie Segura","doi":"10.1126/scisignal.adn6324","DOIUrl":"10.1126/scisignal.adn6324","url":null,"abstract":"<div >Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4–induced transcriptional responses and inhibited the IL-4–induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 858","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439163","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":"The Goldilocks effect of glial tau","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.adt7163","DOIUrl":"10.1126/scisignal.adt7163","url":null,"abstract":"<div >Too much or too little tau in glial cells enables the accumulation of neurotoxic oxidative stress.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 858","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439162","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}