Science Signaling最新文献_第10页

Sensing stretch to suppress appetite 感知伸展以抑制食欲

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adp6031

Wei Wong

引用次数: 0

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition 阻止脂质合成会诱发前列腺癌的 DNA 损伤，并增加 PARP 抑制造成的细胞死亡

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adh1922

Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda

{"title":"Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition","authors":"Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda","doi":"10.1126/scisignal.adh1922","DOIUrl":"10.1126/scisignal.adh1922","url":null,"abstract":"<div >Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 831","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adh1922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541212","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

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation 铁蛋白重亚基通过 ICAM-1 刺激肝星状细胞中的 NLRP3 炎症小体，从而驱动肝脏炎症

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: 10.1126/scisignal.ade4335

Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm

{"title":"The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation","authors":"Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm","doi":"10.1126/scisignal.ade4335","DOIUrl":"10.1126/scisignal.ade4335","url":null,"abstract":"<div >Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of <i>Il1b</i>, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated <i>Il1b</i> expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from <i>Icam1<sup>−/−</sup></i> or <i>Nlrp3<sup>−/−</sup></i> mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 830","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140343125","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

Lipid drops in on Alzheimer’s disease 脂质对老年痴呆症的影响

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: 10.1126/scisignal.adp4951

Amy E. Baek

引用次数: 0

Biasing microglia to help, not hurt 让小胶质细胞助人而非伤人

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: 10.1126/scisignal.adp3241

Leslie K. Ferrarelli

引用次数: 0

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice 小胶质细胞中的葡萄糖酰胺积累会引发 STING 依赖性神经炎症和小鼠神经退行性变

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: https://www.science.org/doi/10.1126/scisignal.adk8249

Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang

{"title":"Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice","authors":"Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang","doi":"https://www.science.org/doi/10.1126/scisignal.adk8249","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.adk8249","url":null,"abstract":"Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson’s disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"298 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586901","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

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery 运动诱导的 BDNF 可促进运动恢复期骨骼肌脂质代谢的 PPARδ 依赖性重编程

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-19 DOI: https://www.science.org/doi/10.1126/scisignal.adh2783

Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan

{"title":"Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery","authors":"Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan","doi":"https://www.science.org/doi/10.1126/scisignal.adh2783","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.adh2783","url":null,"abstract":"Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator–activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific <i>Bdnf</i> knockout (<i>MBKO</i>) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, <i>MBKO</i> mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140203273","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

CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans CXCL17 是 CXCR4 的异构抑制剂，其作用机制涉及糖胺聚糖

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-19 DOI: 10.1126/scisignal.abl3758

Carl W. White, Simon Platt, Laura E. Kilpatrick, Natasha Dale, Rekhati S. Abhayawardana, Sebastian Dekkers, Nicholas D. Kindon, Barrie Kellam, Michael J. Stocks, Kevin D. G. Pfleger, Stephen J. Hill

{"title":"CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans","authors":"Carl W. White, Simon Platt, Laura E. Kilpatrick, Natasha Dale, Rekhati S. Abhayawardana, Sebastian Dekkers, Nicholas D. Kindon, Barrie Kellam, Michael J. Stocks, Kevin D. G. Pfleger, Stephen J. Hill","doi":"10.1126/scisignal.abl3758","DOIUrl":"10.1126/scisignal.abl3758","url":null,"abstract":"<div >CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)–based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 828","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140164518","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 activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P 适配蛋白 STING 的激活取决于它与磷脂 PI4P 的相互作用

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-12 DOI: https://www.science.org/doi/10.1126/scisignal.ade3643

Rutger D. Luteijn, Sypke R. van Terwisga, Jill E. Ver Eecke, Liberty Onia, Shivam A. Zaver, Joshua J. Woodward, Richard W. Wubbolts, David H. Raulet, Frank J. M. van Kuppeveld

{"title":"The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P","authors":"Rutger D. Luteijn, Sypke R. van Terwisga, Jill E. Ver Eecke, Liberty Onia, Shivam A. Zaver, Joshua J. Woodward, Richard W. Wubbolts, David H. Raulet, Frank J. M. van Kuppeveld","doi":"https://www.science.org/doi/10.1126/scisignal.ade3643","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.ade3643","url":null,"abstract":"Activation of the endoplasmic reticulum (ER)–resident adaptor protein STING, a component of a cytosolic DNA–sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses. Through a genome-wide CRISPR interference screen, we found that STING activation required the Golgi-resident protein ACBD3, which promotes the generation of phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network, as well as other PI4P-associated proteins. Appropriate localization and activation of STING at the Golgi apparatus required ACBD3 and the PI4P-generating kinase PI4KB. In contrast, STING activation was enhanced when the lipid-shuttling protein OSBP, which removes PI4P from the Golgi apparatus, was inhibited by the US Food and Drug Administration–approved antifungal itraconazole. The increase in the abundance of STING-activating phospholipids at the trans-Golgi network resulted in the increased production of IFN-β and other cytokines in THP-1 cells. Furthermore, a mutant STING that could not bind to PI4P failed to traffic from the ER to the Golgi apparatus in response to a STING agonist, whereas forced relocalization of STING to PI4P-enriched areas elicited STING activation in the absence of stimulation with a STING agonist. Thus, PI4P is critical for STING activation, and manipulating PI4P abundance may therapeutically modulate STING-dependent immune responses.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140170683","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

Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function 癌症相关成纤维细胞产生的基质结合囊泡会影响内皮细胞的功能。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-12 DOI: 10.1126/scisignal.ade0580

Alice Santi, Emily J. Kay, Lisa J. Neilson, Lynn McGarry, Sergio Lilla, Margaret Mullin, Nikki R. Paul, Frédéric Fercoq, Grigorios Koulouras, Giovanny Rodriguez Blanco, Dimitris Athineos, Susan Mason, Mark Hughes, Gemma Thomson, Yann Kieffer, Colin Nixon, Karen Blyth, Fatima Mechta-Grigoriou, Leo M. Carlin, Sara Zanivan

{"title":"Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function","authors":"Alice Santi, Emily J. Kay, Lisa J. Neilson, Lynn McGarry, Sergio Lilla, Margaret Mullin, Nikki R. Paul, Frédéric Fercoq, Grigorios Koulouras, Giovanny Rodriguez Blanco, Dimitris Athineos, Susan Mason, Mark Hughes, Gemma Thomson, Yann Kieffer, Colin Nixon, Karen Blyth, Fatima Mechta-Grigoriou, Leo M. Carlin, Sara Zanivan","doi":"10.1126/scisignal.ade0580","DOIUrl":"10.1126/scisignal.ade0580","url":null,"abstract":"<div >Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their interaction with immune cells. Mass spectrometry–based proteomics identified proteins transferred from CAFs to ECs, which included plasma membrane receptors. Using THY1 as an example of a transferred plasma membrane–bound protein, we showed that CAF-derived proteins increased the adhesion of a monocyte cell line to ECs. CAFs produced high amounts of matrix-bound EVs, which were the primary vehicles of protein transfer. Hence, our work paves the way for future studies that investigate how CAF-derived matrix-bound EVs influence tumor pathology by regulating the function of neighboring cancer, stromal, and immune cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 827","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111962","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