Science Signaling最新文献

Condensation of cGAS induced by Tyr²⁴² phosphorylation and interaction with MYL6 mediates vascular innate immunity in the lung. Tyr242磷酸化诱导cGAS缩合并与MYL6相互作用介导肺血管先天免疫。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-05-19 DOI: 10.1126/scisignal.adu6757

Bhagwati Joshi, Jagdish Chandra Joshi, Vijay Avin Balaji Raghunathrao, Vigneshwaran Velligiri, Md Zahid Akhter, Peter T Toth, Tejabhiram Yadavalli, Josh Thompson, Somenath Banerjee, Deepak Shukla, Vadim Gaponenko, Yulia Komarova, Dolly Mehta

{"title":"Condensation of cGAS induced by Tyr242 phosphorylation and interaction with MYL6 mediates vascular innate immunity in the lung.","authors":"Bhagwati Joshi, Jagdish Chandra Joshi, Vijay Avin Balaji Raghunathrao, Vigneshwaran Velligiri, Md Zahid Akhter, Peter T Toth, Tejabhiram Yadavalli, Josh Thompson, Somenath Banerjee, Deepak Shukla, Vadim Gaponenko, Yulia Komarova, Dolly Mehta","doi":"10.1126/scisignal.adu6757","DOIUrl":"10.1126/scisignal.adu6757","url":null,"abstract":"An uncontrolled innate immune response to pathogens in the lung causes acute lung injury, in which the cytosolic double-stranded DNA (dsDNA) sensor, cyclic GMP-AMP synthase (cGAS), and its induction of interferon-β (IFN-β) play a crucial role. Given that the vascular endothelium is a point of host contact for both environmental and blood-borne pathogens, we investigated the response of cGAS to dsDNA in endothelial cells in regulating innate immunity in the lung. We found that the phosphorylation of Tyr242 of cGAS facilitated an interaction between cGAS and activated myosin light chain 6 (MYL6), enabling cGAS condensation and activation and leading to IFNB mRNA expression. Furthermore, cGAS binding to dsDNA rapidly increased intracellular Ca2+ in a manner requiring the ER Ca2+ sensor STIM1 to activate MYL6 for cGAS condensation. In cGAS-deficient mice, expression of wild-type cGAS or a phosphomimetic cGAS mutant in the lung endothelium was sufficient to enhance signaling downstream of cGAS, induce neutrophil recruitment, and exacerbate lung damage in response to Pseudomonas aeruginosa infection. Our findings suggest a role for phosphorylation of Tyr242 in cGAS in the endothelium as critical for inducing innate immune responses to pathogens and contributing to acute lung injury.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 938","pages":"eadu6757"},"PeriodicalIF":6.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13681457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977043","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}

引用次数: 0

Treating depression through G proteins. 通过G蛋白治疗抑郁症。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-05-12 DOI: 10.1126/scisignal.aei6144

Leslie K Ferrarelli

引用次数: 0

Transcytosis-mediated anterograde transport of the receptor TrkA mediates the formation of presynaptic sites in sympathetic neurons. 胞吞介导的受体TrkA的顺行转运介导交感神经元突触前位点的形成。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-05-12 DOI: 10.1126/scisignal.aea7078

Guillermo Moya-Alvarado, Sebastian M Markert, Sumana Raychaudhuri, Matthew Tachoute, Shigeki Watanabe, Rejji Kuruvilla

{"title":"Transcytosis-mediated anterograde transport of the receptor TrkA mediates the formation of presynaptic sites in sympathetic neurons.","authors":"Guillermo Moya-Alvarado, Sebastian M Markert, Sumana Raychaudhuri, Matthew Tachoute, Shigeki Watanabe, Rejji Kuruvilla","doi":"10.1126/scisignal.aea7078","DOIUrl":"10.1126/scisignal.aea7078","url":null,"abstract":"In neurons, many membrane proteins that are synthesized in the cell body must be efficiently delivered to axons to regulate neuronal connectivity. Transcytosis is an atypical transport mode in which membrane proteins internalized from soma membranes are transported to axons in an anterograde fashion. Here, we characterized the trafficking dynamics and mechanism of transcytosis of the receptor TrkA from the soma in response to nerve growth factor (NFG) signaling at the axon in mouse sympathetic neurons. Live imaging and electron microscopy of compartmentalized cultures revealed that soma surface-derived TrkA proteins underwent dynamic transport in axons, with changes in speed, direction, and the vesicular organelles that carried them as they moved from proximal to distal axon compartments. In mice, soma surface-labeled TrkA proteins were observed in sympathetic nerve terminals, demonstrating that transcytosis occurs in vivo. Transcytosed TrkA proteins were enriched at presynaptic varicosities, bouton-like structures that store and release neurotransmitters. Disrupting its transcytosis by introducing a point mutation into TrkA reduced the number and size of presynaptic sites and decreased synaptic transmission in vivo and in culture. These findings provide mechanistic insight into an atypical mode of receptor trafficking and demonstrate its physiological relevance in sympathetic neuron connectivity in mice.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 937","pages":"eaea7078"},"PeriodicalIF":6.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147935029","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}

引用次数: 0

The transmembrane domain structure of TNFR1 suppresses ligand-independent autoactivation but is not required for TNF-induced signaling. TNFR1的跨膜结构域结构抑制与配体无关的自激活，但不是tnf诱导的信号传导所必需的。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-05-12 DOI: 10.1126/scisignal.adz0203

Panxue Wang, Assaf Elazar, Jonathan Y Weinstein, Nicholas J Chandler, Sarel J Fleishman, Melissa J Call, Matthew E Call, John Silke

{"title":"The transmembrane domain structure of TNFR1 suppresses ligand-independent autoactivation but is not required for TNF-induced signaling.","authors":"Panxue Wang, Assaf Elazar, Jonathan Y Weinstein, Nicholas J Chandler, Sarel J Fleishman, Melissa J Call, Matthew E Call, John Silke","doi":"10.1126/scisignal.adz0203","DOIUrl":"10.1126/scisignal.adz0203","url":null,"abstract":"Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, and it predominantly signals by binding to TNF receptor 1 (TNFR1), a type I single-spanning transmembrane protein that is thought to exist primarily as monomers and dimers. The binding of trimeric ligands induces the formation of signaling-competent trimers and higher-order oligomers that lead to full activation of downstream NF-κB and MAPK signaling pathways. Several TNFR superfamily members, including TNFR1, can form trimeric structures through their transmembrane domains (TMDs). For Fas and DR5, these structures support ligand-induced activation, and ectodomain (ECD) interactions prevent ligand-independent signaling. To explore the structures' role in TNFR1 activation, we replaced the native TNFR1 TMDs with natural and de novo designed versions that formed stable and specific structures of defined monomeric or oligomeric states. We found that none of these TMD variant receptors displayed defects in TNF-induced signaling in mouse fibroblasts, but some showed increased autoactivation in the absence of ligand, particularly where the engineered TMD sequence prevented self-association. Autoactivation depended on intracellular death domain interactions and was exacerbated by a disease-associated mutation but was unaffected by mutation in the preligand assembly domain. Our results demonstrate that, unlike for other TNFR family members, no specific oligomeric TMD structure is required for normal, ligand-induced activation of TNFR1, but self-association through the native TMD may instead act together with ECD interactions to help suppress ligand-free autoactivation.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 937","pages":"eadz0203"},"PeriodicalIF":6.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147935042","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}

引用次数: 0

Hour-scale single-molecule imaging reveals dynamic assembly of the Wnt co-receptors LRP6 and ROR2 into common signalosomes. 小时尺度的单分子成像揭示了Wnt共受体LRP6和ROR2在共同信号小体中的动态组装。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-03 DOI: 10.1126/scisignal.adr8141

Michael Philippi, Julia Dohle, Isabelle Watrinet, Michael Holtmannspötter, Yi Miao, Jinye Li, Oliver Birkholz, Ulrich Rothbauer, K Christopher Garcia, Rainer Kurre, Jacob Piehler, Changjiang You

{"title":"Hour-scale single-molecule imaging reveals dynamic assembly of the Wnt co-receptors LRP6 and ROR2 into common signalosomes.","authors":"Michael Philippi, Julia Dohle, Isabelle Watrinet, Michael Holtmannspötter, Yi Miao, Jinye Li, Oliver Birkholz, Ulrich Rothbauer, K Christopher Garcia, Rainer Kurre, Jacob Piehler, Changjiang You","doi":"10.1126/scisignal.adr8141","DOIUrl":"10.1126/scisignal.adr8141","url":null,"abstract":"Wnt ligands stimulate β-catenin-dependent (canonical) or β-catenin-independent (noncanonical) signaling, depending on which co-receptors are recruited to the Wnt receptor FZD. Both pathways are initiated by receptor oligomerization into signalosomes and involve a largely overlapping set of downstream effectors. To resolve the assembly of Wnt signalosomes with high spatiotemporal resolution for extended times, we developed single-molecule tracking and localization microscopy based on labeling with reversibly binding nanobodies (rbTALM). We engineered nanobody-tag pairs with finely tuned binding affinities to ensure single-molecule tracking with high fidelity while also permitting continuous exchange of photobleached labels. Multicolor rbTALM imaging enabled simultaneous tracking and super-resolution imaging of three different tagged Wnt co-receptors in the same cell for more than 1 hour at video rate. Time-lapse correlation analyses uncovered cooperative association of canonical (LRP6) and noncanonical (ROR2) Wnt co-receptors with FZD8 into a common, hybrid Wnt signalosome. These findings demonstrate the potential for rbTALM imaging for exploring nanoscale dynamics across millisecond to hour timescales and for deciphering the molecular dynamics that underlie signaling complex formation.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 927","pages":"eadr8141"},"PeriodicalIF":6.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349630","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}

引用次数: 0

Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors. 葡萄糖代谢通过糖基化的局部信号因子维持结直肠癌中异常的STAT3信号。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-03-03 DOI: 10.1126/scisignal.adz6443

Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah

{"title":"Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.","authors":"Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah","doi":"10.1126/scisignal.adz6443","DOIUrl":"10.1126/scisignal.adz6443","url":null,"abstract":"The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 927","pages":"eadz6443"},"PeriodicalIF":6.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349590","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}

引用次数: 0

Acetate enhances long-term memory in female mice by sex-, context-, and brain region-specific epigenetic and transcriptional remodeling. 醋酸酯通过性别、环境和脑区域特异性表观遗传和转录重塑增强雌性小鼠的长期记忆。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.aec0496

Erica M Periandri, Kala M Dodson, Francisca N de Luna Vitorino, Benjamin A Garcia, Karl M Glastad, Gabor Egervari

引用次数: 0

Temporal proteomic and phosphoproteomic dynamics during neuronal differentiation in the reference iPSC line KOLF2.1J. 参考iPSC细胞系KOLF2.1J神经元分化过程中的时间蛋白质组学和磷酸化蛋白质组学动态。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.adx8680

Ying Hao, Ziyi Li, Erika Lara, Daniel M Ramos, Marianita Santiana, Benjamin Jin, Jacob Epstein, Isabelle Kowal, Jasmin Camacho, Nicole Carmiol, Jae-Hyeon Park, Aleksandra Beylina, Linda G Yang, Jessica T Root, Dylan C Sacks, Paige Jarreau, Cory A Weller, Sydney Klaisner, Laurel A Screven, Caroline B Pantazis, Mike A Nalls, Priyanka Narayan, Luigi Ferrucci, Andrew B Singleton, Michael E Ward, Mark R Cookson, Yue Andy Qi

{"title":"Temporal proteomic and phosphoproteomic dynamics during neuronal differentiation in the reference iPSC line KOLF2.1J.","authors":"Ying Hao, Ziyi Li, Erika Lara, Daniel M Ramos, Marianita Santiana, Benjamin Jin, Jacob Epstein, Isabelle Kowal, Jasmin Camacho, Nicole Carmiol, Jae-Hyeon Park, Aleksandra Beylina, Linda G Yang, Jessica T Root, Dylan C Sacks, Paige Jarreau, Cory A Weller, Sydney Klaisner, Laurel A Screven, Caroline B Pantazis, Mike A Nalls, Priyanka Narayan, Luigi Ferrucci, Andrew B Singleton, Michael E Ward, Mark R Cookson, Yue Andy Qi","doi":"10.1126/scisignal.adx8680","DOIUrl":"10.1126/scisignal.adx8680","url":null,"abstract":"Induced pluripotent stem cell (iPSC)-derived neurons are a powerful tool with which to investigate both neuronal development and neurodegenerative diseases. Here, we applied quantitative proteomic and phosphoproteomic analyses to profile the neuronal differentiation of the KOLF2.1J iPSC line, the first reference line of the iPSC Neurodegenerative Disease Initiative (iNDI) project. We developed an automated workflow enabling high-coverage enrichment of proteins and phosphorylated peptides, which revealed molecular signatures during the differentiation of iPSC-derived neurons. Proteomic data highlighted distinct changes in mitochondrial pathways throughout the course of differentiation, whereas phosphoproteomic data revealed specific regulatory dynamics in GTPase-mediated signaling pathways and microtubule proteins. Additionally, phosphosite dynamics were not correlated to changes in protein abundance, particularly in processes related to axon functions and RNA transport. We measured the dynamic changes in kinases that are critical for neuronal development and maturation and developed an interactive web app to visualize the temporal landscape dynamics of protein and phosphosite abundance. By establishing baselines of proteomic and phosphoproteomic profiles for neuronal differentiation, this dataset is a valuable resource for future research into neuronal development and neurodegenerative diseases using this reference iPSC line.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 926","pages":"eadx8680"},"PeriodicalIF":6.6,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286003","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}

引用次数: 0

Fungi facilitate gut healing. 真菌促进肠道愈合。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.aeg5547

Annalisa M VanHook

引用次数: 0

Metabolic alterations after traumatic neural injury: Mechanistic insights and potential translational targets for axon regeneration. 创伤性神经损伤后的代谢改变：轴突再生的机制见解和潜在的翻译靶点。

IF 6.6 1区生物学

Science Signaling Pub Date : 2026-02-24 DOI: 10.1126/scisignal.adx9003

Qianqian Cao, Wenwen Zhao, Junjie Yan, Stephane Belin, Bin Yu, Homaira Nawabi, Susu Mao

{"title":"Metabolic alterations after traumatic neural injury: Mechanistic insights and potential translational targets for axon regeneration.","authors":"Qianqian Cao, Wenwen Zhao, Junjie Yan, Stephane Belin, Bin Yu, Homaira Nawabi, Susu Mao","doi":"10.1126/scisignal.adx9003","DOIUrl":"10.1126/scisignal.adx9003","url":null,"abstract":"Metabolism not only provides essential substances and energy for cells through catabolism and anabolism but also exerts broader regulatory roles through metabolic enzymes and products that influence gene expression, thereby maintaining homeostasis. Upon neuronal injury, metabolic changes in both neurons and supporting cells influence neuronal survival and regeneration by regulating energy supply, substrate availability, regeneration-related gene expression, and cell-cell metabolic interactions. Axon regeneration is a key process in neural repair after injury. Beyond the nervous system itself, systemic factors such as diet, exercise, circadian rhythms, and psychological stress also play crucial roles in axon regeneration through interorgan metabolic communication and microbiota-host metabolic cross-talk. In this Review, we summarize advances in understanding metabolic alterations during axon regeneration, with a focus on glycometabolism, lipid metabolism, protein degradation, mitochondrial activity, and systemic factor-driven metabolic cross-talk between nervous and non-nervous systems. We also highlight the therapeutic potential of metabolites themselves, analyze distinct metabolic responses after injury in the peripheral and central nervous systems, and discuss their spatiotemporal dynamics and cell type specificity. Last, we propose that successful neural repair requires the establishment of a systemic pro-regenerative state throughout the entire body.","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"19 926","pages":"eadx9003"},"PeriodicalIF":6.6,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147285962","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}

引用次数: 0