Science Signaling最新文献

{"title":"LIPID MAPS: Powering discovery in lipidomics","authors":"Lauren Cockayne,&nbsp;Matthew J. Conroy,&nbsp;Chetin Baloglu,&nbsp;Eoin Fahy,&nbsp;Gerhard Hagn,&nbsp;Oswald Quehenberger,&nbsp;Aaron M. Armando,&nbsp;Gabriele Lombardi Bendoula,&nbsp;Jean-Marie Galano,&nbsp;Ángel Sánchez-Illana,&nbsp;Thierry Durand,&nbsp;Nadja Kampschulte,&nbsp;Paul D. Kennedy,&nbsp;Miguel Gijón,&nbsp;Hiroshi Tsugawa,&nbsp;Makoto Arita,&nbsp;Kirk Maxey,&nbsp;Meghan Truskowski,&nbsp;Ondrej Kuda,&nbsp;Shazia Khan,&nbsp;Natalie Z. M. Homer,&nbsp;Yuki Matsuzawa,&nbsp;Rosario Domingues,&nbsp;Peter J. Meikle,&nbsp;Corey Giles,&nbsp;Kevin Huynh,&nbsp;Robert C. Murphy,&nbsp;Zidan Wang,&nbsp;Yu Xia,&nbsp;Xue Li Guan,&nbsp;Kim Ekroos,&nbsp;Gerhard Liebisch,&nbsp;Alfred H. Merrill Jr.,&nbsp;Andrea F. Lopez-Clavijo,&nbsp;Dominic Campopiano,&nbsp;Craig E. Wheelock,&nbsp;Shankar Subramaniam,&nbsp;Robert Andrews,&nbsp;Laura Goracci,&nbsp;Zhixu Ni,&nbsp;Maria Fedorova,&nbsp;Simon Andrews,&nbsp;William Griffiths,&nbsp;Ruth Andrew,&nbsp;Edward A. Dennis,&nbsp;Valerie B. O’Donnell","doi":"10.1126/scisignal.aeg3389","DOIUrl":"10.1126/scisignal.aeg3389","url":null,"abstract":"<div >As lipidomics approaches its 25th anniversary, we explore how lipid research has matured over the years while highlighting emerging innovations that are expanding our ability to study these diverse, life-critical biomolecules. In particular, we showcase the community-driven, open-access databases, software, and educational resources made freely available through the ELIXIR Core Data Resource LIPID MAPS for the benefit of both established and new researchers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 936","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827051","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":"A Caenorhabditis elegans spatiotemporal proximity atlas reveals the MAPK p38 as a generator of phenotypic plasticity in vivo","authors":"Wang Yuan,&nbsp;Luke A. Nunamaker,&nbsp;Yi M. Weaver,&nbsp;Benjamin P. Weaver","doi":"10.1126/scisignal.aeb4530","DOIUrl":"10.1126/scisignal.aeb4530","url":null,"abstract":"<div >Phenotypic plasticity, the ability to change diverse traits without altering genomic information, is fundamental for organismal adaptations to changing environments. The mitogen-activated protein kinase (MAPK) pathway plays a key role in cellular adaptations to changing environments. To analyze the contributions of the MAPK p38 and its interaction partners to phenotypic plasticity in an animal, we established an in vivo proximity labeling proteomics method called ContinuumID. With this method, we built an atlas of PMK-1 physical interactors during development, in specific tissues, and during exposure to osmotic, ultraviolet, or oxidative stressors. We identified multiple stable and dynamic developmental stage–, tissue-, and stress-specific PMK-1 interactors. Phenotypic analyses of animals in which specific interactors were knocked down revealed considerable variability of diverse PMK-1–dependent outputs. These included target gene expression, survival under stress, lysosomal homeostasis during development, and neuronal integrity during aging. PMK-1 interactors exerted positive, negative, and neutral contributions to these outputs within and across functional pathways. Comparing developmental and stress-induced activation of PMK-1 and the regulatory functions of its interactors revealed that PMK-1 integrates the regulation of highly conserved protein synthesis and RNA processing pathways with that of rapidly changing signaling and metabolic adaptations to confer distinct survival advantages or disadvantages during stress.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 936","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827050","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":"SMAD1-mediated induction of peripheral CRH after nerve injury promotes neuropathic pain by activating spinal CRHR2","authors":"Cheng He,&nbsp;Ling-Jie Ma,&nbsp;Yuan-Yuan Fu,&nbsp;Ke-Chen Zhang,&nbsp;Ye Tao,&nbsp;Xiao Wei,&nbsp;Yong-Liang Shen,&nbsp;Juan Wang,&nbsp;Yong-Jing Gao,&nbsp;Zhi-Jun Zhang","doi":"10.1126/scisignal.aeb3953","DOIUrl":"10.1126/scisignal.aeb3953","url":null,"abstract":"<div >Neuropathic pain is a debilitating condition that lacks effective treatments. Corticotropin-releasing hormone (CRH) is associated with the central neural circuits involved in stress and pain. Here, we identified a peripheral CRH–mediated signaling axis in dorsal root ganglion (DRG) and spinal neurons underlying neuropathic pain. Spared nerve injury (SNI) in male mice increased the abundance of CRH in small- and medium-diameter DRG neurons, specifically in their central terminals in the spinal dorsal horn. DRG-specific knockdown of CRH alleviated neuropathic pain. SNI increased <i>Crh</i> expression by inducing the binding of the transcription factor SMAD1 to the <i>Crh</i> promoter. Silencing SMAD1 in the DRG reduced neuropathic pain symptoms, which was accompanied by a decrease in the amount of CRH in the DRG tissue. Pharmacological antagonism of CRH receptor 2 (CRHR2), but not of CRHR1, attenuated neuropathic pain and suppressed the activation of spinal neurons and glia. Spinal CRHR2 predominantly localized to excitatory neurons and somatostatin-positive interneurons in the superficial dorsal horn. These findings reveal a SMAD1-CRH-CRHR2 axis in DRG-to-spine signaling that promotes neuropathic pain and suggest that CRHR2 antagonists be explored for its management.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 935","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787436","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":"An inflammation memento","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.aei2458","DOIUrl":"10.1126/scisignal.aei2458","url":null,"abstract":"<div >Colitis imposes epigenetic changes that prime colonic stem cells for tumor growth.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 935","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787353","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":"Deep secretome analysis reveals the effects of LiCl on fibroangiogenic remodeling in coculture and mouse models of peritoneal dialysis","authors":"Juan Manuel Sacnun,&nbsp;Lisa Daniel-Fischer,&nbsp;Isabel J. Sobieszek,&nbsp;Anja Wagner,&nbsp;Markus Unterwurzacher,&nbsp;Fabian Eibensteiner,&nbsp;Maria Bartosova Medvid,&nbsp;Iva Marinovic,&nbsp;Elisabeth Lang,&nbsp;Florian M. Wiesenhofer,&nbsp;Sophie Bromberger,&nbsp;Leonore Müller,&nbsp;Klaus Kaczirek,&nbsp;Andreas Vychytil,&nbsp;Claus Peter Schmitt,&nbsp;Seth L. Alper,&nbsp;Christoph Aufricht,&nbsp;Rebecca Herzog,&nbsp;Klaus Kratochwill","doi":"10.1126/scisignal.ady2586","DOIUrl":"10.1126/scisignal.ady2586","url":null,"abstract":"<div >For patients with kidney failure, peritoneal dialysis (PD) is an alternative kidney replacement therapy to hemodialysis. Long-term PD efficacy is limited by multicellular pathologies induced by the hyperosmotic PD fluids, including vasculopathy and fibroangiogenic remodeling of the peritoneum, which lack targeted pharmacological interventions. We developed a deep secretome profiling workflow in a coculture system using a human peritoneal mesothelial cell line and primary human lymphatic endothelial cells to characterize the influence of PD fluid on communication between these cell types. This approach uncovered extracellular and intracellular signaling patterns absent in standard monocultures and identified 1910 human proteins that revealed extracellular regulatory processes central to PD-associated peritoneal pathology. Integration of the coculture secretome and cellular proteomes with effluent and plasma proteomes derived from patients with PD revealed cell type–specific signaling networks and groups of proteins correlating with clinical parameters such as ultrafiltration capacity, transport kinetics, and inflammation. Functional validation demonstrated that lithium chloride supplementation partially counteracted fibroangiogenic signaling and affected key PD fluid–induced processes, including PDGFC-driven lymphangiogenesis, syndecan-4 ectodomain shedding by endothelial cells, and a mesothelial switch from NOTCH1 to NOTCH3 synthesis. These findings suggest new potential pharmacological strategies to mitigate peritoneal fibrosis and vasculopathy, offering a framework for future therapeutic innovation in PD and beyond.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 935","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787369","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":"mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation","authors":"Keita Uchida,&nbsp;Emily A. Scarborough,&nbsp;Elizabeth Pruzinsky,&nbsp;Kathlyene R. Stone,&nbsp;Hali Hartman,&nbsp;Daniel P. Kelly,&nbsp;Jonathan J. Edwards,&nbsp;Izhak Kehat,&nbsp;Benjamin L. Prosser","doi":"10.1126/scisignal.adu5769","DOIUrl":"10.1126/scisignal.adu5769","url":null,"abstract":"<div >Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E–binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK–dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK–dependent phosphorylation of 4EBP1 at Ser⁶⁴ was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 934","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787393","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":"Activation of the NLRP3 inflammasome in osteoclasts is suppressed by a Tmem178-dependent mechanism that restricts Ca2+ influx","authors":"Khushpreet Kaur,&nbsp;Yael Alippe,&nbsp;Chun Wang,&nbsp;Nicholas P. Semenkovich,&nbsp;Mohamed G. Hassan,&nbsp;Saumya Bhagat,&nbsp;Kunjan Khanna,&nbsp;Yongjia Li,&nbsp;Nitin Pokhrel,&nbsp;Timothy Peterson,&nbsp;Erica L. Scheller,&nbsp;Deborah J. Veis,&nbsp;Yousef Abu-Amer,&nbsp;Roberta Faccio,&nbsp;Gabriel Mbalaviele","doi":"10.1126/scisignal.aea2753","DOIUrl":"10.1126/scisignal.aea2753","url":null,"abstract":"<div >Activation of the NLRP3 inflammasome can drive bone resorption by osteoclasts in various inflammatory conditions. Here, we identified Tmem178, a protein that restrains Ca²⁺ fluxes by limiting SOCE activation, as an inhibitor of NLRP3 inflammasome activation and the bone-resorbing activity of osteoclasts. We found that NLRP3 abundance gradually decreased during osteoclastogenesis but was restored by treatment with the bacterial product LPS. LPS and the NLRP3 activator nigericin stimulated this inflammasome in macrophages, as expected, but not in osteoclasts or their lineage-committed precursors. This differential NLRP3 activation was due to Tmem178, a protein abundant in osteoclasts that suppressed NLRP3 inflammasome nucleation. Accordingly, NLRP3 inflammasome activation was robust in osteoclasts lacking Tmem178 or in wild-type osteoclasts exposed to high Ca²⁺ concentrations. In vivo studies demonstrated that inflammasome formation was enhanced under conditions in which osteoclasts efficiently release Ca²⁺ from bone and that deletion of <i>Nlrp3</i> rescued the osteopenic phenotype characteristic of <i>Tmem178^−/−</i> mice. Thus, our results indicate that Tmem178 potently restricts Ca²⁺ influx in osteoclasts, thereby suppressing NLRP3 inflammasome activation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 934","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787312","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":"Keeping inflammasomes in check during bone resorption","authors":"Caroline Schmidt,&nbsp;Ulf Wagner","doi":"10.1126/scisignal.aeg1707","DOIUrl":"10.1126/scisignal.aeg1707","url":null,"abstract":"<div >Ca²⁺ flux is a key trigger of NLRP3 inflammasome activation, but bone-resorbing osteoclasts operate in a Ca²⁺-rich environment created during bone resorption. In this issue of <i>Science Signaling</i>, Kaur <i>et al.</i> reveal that osteoclasts prevent inflammasome activation by limiting Ca²⁺ influx through the membrane protein Tmem178, thereby protecting bone from excessive resorption driven by inflammatory signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 934","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787429","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":"High glucose impairs cognitive function through Creb3 O-GlcNAcylation and increased lactate production","authors":"Jingxi Xu,&nbsp;Xing Yang,&nbsp;Jingxue Cao,&nbsp;Yuqi Hao,&nbsp;Rongrong Nie,&nbsp;Qiongsui Zhong,&nbsp;Yun Gao,&nbsp;Ya Hui,&nbsp;Liuyu Kuang,&nbsp;Yuanmei Zhong,&nbsp;Biwen Mo,&nbsp;Xiaoyun Zeng,&nbsp;Tianpeng Zheng","doi":"10.1126/scisignal.adx4313","DOIUrl":"10.1126/scisignal.adx4313","url":null,"abstract":"<div >The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation. Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose–induced cognitive impairment, a prevalent complication of diabetes. A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes. High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene <i>Ldha</i>, which encodes the enzyme lactate dehydrogenase. As a result, lactate production was increased during glycolysis, triggering neuronal apoptosis and cognitive dysfunction in mouse models of type 1 and 2 diabetes. Expression of a Creb3 mutant that could not be O-GlcNAcylated at Ser³²⁵ or competitive blockade of the O-GlcNAcylation of Ser³²⁵ in Creb3 with a short peptide alleviated these effects. This study elucidates a mechanistic link between high glucose–induced Creb3 O-GlcNAcylation and Ldha-mediated lactate production, offering a potential therapeutic strategy for managing diabetes-related cognitive dysfunction.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 933","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669058","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":"Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons","authors":"Jose Norberto S. Vargas,&nbsp;Anna-Leigh Brown,&nbsp;Kai Sun,&nbsp;Cathleen Hagemann,&nbsp;Bethany Geary,&nbsp;David Villarroel-Campos,&nbsp;Sam Bryce-Smith,&nbsp;Matteo Zanovello,&nbsp;Madeline Lombardo,&nbsp;Stan Majewski,&nbsp;Andrew Tosolini,&nbsp;Maria Secrier,&nbsp;Matthew J. Keuss,&nbsp;Andrea Serio,&nbsp;James N. Sleigh,&nbsp;Pietro Fratta,&nbsp;Giampietro Schiavo","doi":"10.1126/scisignal.adx6752","DOIUrl":"10.1126/scisignal.adx6752","url":null,"abstract":"<div >The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i³ LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i³ LMNs revealed that BDNF temporally regulated the expression and RNA stability of functionally distinct transcriptional programs that included regeneration-associated gene sets, further enhancing their expression. BDNF also regulated the phosphorylation of multiple proteins involved in cytoskeletal dynamics. In compartmentalized cultures of neurons, in which microfluidic chambers isolate somata from their axons, BDNF-induced regeneration depended on axon-specific activation of the ERK-RSK-S6K kinase pathway. The findings show that extrinsic BDNF signaling coordinates intrinsic axon-regeneration programs and highlight the role of spatially regulated kinase activation in this process.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 933","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669059","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}