Science Signaling最新文献_第6页

Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes 葡萄糖-氧气剥夺限制了人类单核细胞中 HMGCR 的功能和 Rac1 的前酰化，并激活了 NLRP3 炎症小体。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-16 DOI: 10.1126/scisignal.add8913

Nora Raulien, Kathleen Friedrich, Sarah Strobel, Stefanie Raps, Friederike Hecker, Matthias Pierer, Erik Schilling, Elke Lainka, Tilmann Kallinich, Sven Baumann, Katarina Fritz-Wallace, Ulrike Rolle-Kampczyk, Martin von Bergen, Achim Aigner, Alexander Ewe, Georg Schett, Michael Cross, Manuela Rossol, Ulf Wagner

{"title":"Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes","authors":"Nora Raulien, Kathleen Friedrich, Sarah Strobel, Stefanie Raps, Friederike Hecker, Matthias Pierer, Erik Schilling, Elke Lainka, Tilmann Kallinich, Sven Baumann, Katarina Fritz-Wallace, Ulrike Rolle-Kampczyk, Martin von Bergen, Achim Aigner, Alexander Ewe, Georg Schett, Michael Cross, Manuela Rossol, Ulf Wagner","doi":"10.1126/scisignal.add8913","DOIUrl":"10.1126/scisignal.add8913","url":null,"abstract":"<div >Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 845","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629165","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

Kv1.3-induced hyperpolarization is required for efficient Kaposi’s sarcoma–associated herpesvirus lytic replication Kv1.3诱导的超极化是卡波西肉瘤相关疱疹病毒高效溶解复制所必需的。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-16 DOI: 10.1126/scisignal.adg4124

Holli Carden, Katherine L. Harper, Timothy J. Mottram, Oliver Manners, Katie L. Allott, Mark L. Dallas, David J. Hughes, Jonathan D. Lippiat, Jamel Mankouri, Adrian Whitehouse

{"title":"Kv1.3-induced hyperpolarization is required for efficient Kaposi’s sarcoma–associated herpesvirus lytic replication","authors":"Holli Carden, Katherine L. Harper, Timothy J. Mottram, Oliver Manners, Katie L. Allott, Mark L. Dallas, David J. Hughes, Jonathan D. Lippiat, Jamel Mankouri, Adrian Whitehouse","doi":"10.1126/scisignal.adg4124","DOIUrl":"10.1126/scisignal.adg4124","url":null,"abstract":"<div >Kaposi’s sarcoma–associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked directly to the development of Kaposi’s sarcoma. KSHV establishes a latent infection in B cells, which can be reactivated to initiate lytic replication, producing infectious virions. Using pharmacological and genetic silencing approaches, we showed that the voltage-gated K<sup>+</sup> channel K<sub>v</sub>1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of K<sub>v</sub>1.3 and led to enhanced K<sup>+</sup> channel activity and hyperpolarization of the B cell membrane. Enhanced K<sub>v</sub>1.3 activity promoted intracellular Ca<sup>2+</sup> influx, leading to the Ca<sup>2+</sup>-driven nuclear localization of KSHV RTA and host nuclear factor of activated T cells (NFAT) proteins and subsequently increased the expression of NFAT1 target genes. KSHV lytic replication and infectious virion production were inhibited by K<sub>v</sub>1.3 blockers or silencing. These findings highlight K<sub>v</sub>1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 845","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adg4124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629166","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

Pyroptosis does damage control Pyroptosis 进行损害控制。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-16 DOI: 10.1126/scisignal.adr5475

Amy E. Baek

引用次数: 0

A metabolic regulator for parietal cells 顶细胞的代谢调节器

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-09 DOI: 10.1126/scisignal.adr4497

Annalisa M. VanHook

引用次数: 0

An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis 抑制 TGF-β1 从潜伏细胞外基质复合物中释放的抗体可减轻肾脏纤维化的进展。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-09 DOI: 10.1126/scisignal.adn6052

Justin W. Jackson, Frederick C. Streich Jr., Ajai Pal, George Coricor, Chris Boston, Christopher T. Brueckner, Kaleigh Canonico, Christopher Chapron, Shaun Cote, Kevin B. Dagbay, Francis T. Danehy Jr., Mania Kavosi, Sandeep Kumar, Susan Lin, Christopher Littlefield, Kailyn Looby, Rohan Manohar, Constance J. Martin, Marcie Wood, Agatha Zawadzka, Stefan Wawersik, Samantha B. Nicholls, Abhishek Datta, Alan Buckler, Thomas Schürpf, Gregory J. Carven, Mohammed Qatanani, Adam I. Fogel

{"title":"An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis","authors":"Justin W. Jackson, Frederick C. Streich Jr., Ajai Pal, George Coricor, Chris Boston, Christopher T. Brueckner, Kaleigh Canonico, Christopher Chapron, Shaun Cote, Kevin B. Dagbay, Francis T. Danehy Jr., Mania Kavosi, Sandeep Kumar, Susan Lin, Christopher Littlefield, Kailyn Looby, Rohan Manohar, Constance J. Martin, Marcie Wood, Agatha Zawadzka, Stefan Wawersik, Samantha B. Nicholls, Abhishek Datta, Alan Buckler, Thomas Schürpf, Gregory J. Carven, Mohammed Qatanani, Adam I. Fogel","doi":"10.1126/scisignal.adn6052","DOIUrl":"10.1126/scisignal.adn6052","url":null,"abstract":"<div >Inhibitors of the transforming growth factor–β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β–binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody’s selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 844","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564986","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

More Velcro for the TGF-β1 straitjacket: A new antibody straps latent TGF-β1 to the matrix 为 TGF-β1 紧身衣提供更多魔术贴：一种新型抗体将潜伏的 TGF-β1 绑在基质上。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-09 DOI: 10.1126/scisignal.ado5279

Boris Hinz

引用次数: 0

Insulated by opioids 被阿片类药物隔绝

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-02 DOI: 10.1126/scisignal.adr3505

Leslie K. Ferrarelli

引用次数: 0

Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling 经过改造的迷你 G 蛋白会阻止同源 GPCR 的内化，并破坏下游细胞内信号传导。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-02 DOI: 10.1126/scisignal.abq7038

Yusman Manchanda, Liliane ElEid, Affiong I. Oqua, Zenouska Ramchunder, Jiyoon Choi, Maria M. Shchepinova, Guy A. Rutter, Asuka Inoue, Edward W. Tate, Ben Jones, Alejandra Tomas

{"title":"Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling","authors":"Yusman Manchanda, Liliane ElEid, Affiong I. Oqua, Zenouska Ramchunder, Jiyoon Choi, Maria M. Shchepinova, Guy A. Rutter, Asuka Inoue, Edward W. Tate, Ben Jones, Alejandra Tomas","doi":"10.1126/scisignal.abq7038","DOIUrl":"10.1126/scisignal.abq7038","url":null,"abstract":"<div >Mini-G proteins are engineered, thermostable variants of Gα subunits designed to stabilize G protein–coupled receptors (GPCRs) in their active conformations. Because of their small size and ease of use, they are popular tools for assessing GPCR behaviors in cells, both as reporters of receptor coupling to Gα subtypes and for cellular assays to quantify compartmentalized signaling at various subcellular locations. Here, we report that overexpression of mini-G proteins with their cognate GPCRs disrupted GPCR endocytic trafficking and associated intracellular signaling. In cells expressing the Gα<sub>s</sub>-coupled GPCR glucagon-like peptide 1 receptor (GLP-1R), coexpression of mini-G<sub>s</sub>, a mini-G protein derived from Gα<sub>s</sub>, blocked β-arrestin 2 recruitment and receptor internalization and disrupted endosomal GLP-1R signaling. These effects did not involve changes in receptor phosphorylation or lipid nanodomain segregation. Moreover, we found that mini-G proteins derived from Gα<sub>i</sub> and Gα<sub>q</sub> also inhibited the internalization of GPCRs that couple to them. Finally, we developed an alternative intracellular signaling assay for GLP-1R using a nanobody specific for active Gα<sub>s</sub>:GPCR complexes (Nb37) that did not affect GLP-1R internalization. Our results have important implications for designing methods to assess intracellular GPCR signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 843","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494037","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

YAP represses the TEAD–NF-κB complex and inhibits the growth of clear cell renal cell carcinoma YAP 可抑制 TEAD-NF-κB 复合物并抑制透明细胞肾细胞癌的生长。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-02 DOI: 10.1126/scisignal.adk0231

Zhongbo Li, Peng Su, Miao Yu, Xufeng Zhang, Yaning Xu, Tianwei Jia, Penghe Yang, Chenmiao Zhang, Yanan Sun, Xin Li, Huijie Yang, Yinlu Ding, Ting Zhuang, Haiyang Guo, Jian Zhu

{"title":"YAP represses the TEAD–NF-κB complex and inhibits the growth of clear cell renal cell carcinoma","authors":"Zhongbo Li, Peng Su, Miao Yu, Xufeng Zhang, Yaning Xu, Tianwei Jia, Penghe Yang, Chenmiao Zhang, Yanan Sun, Xin Li, Huijie Yang, Yinlu Ding, Ting Zhuang, Haiyang Guo, Jian Zhu","doi":"10.1126/scisignal.adk0231","DOIUrl":"10.1126/scisignal.adk0231","url":null,"abstract":"<div >The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB–target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner—that is, by activating YAP—may be a strategy for slowing tumor growth in patients.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 843","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adk0231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494039","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

Tweaking synaptic plasticity: Deciphering the role of WWC1 in memory opens new therapeutic horizons 调整突触可塑性：解密 WWC1 在记忆中的作用开辟了新的治疗前景。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-06-25 DOI: 10.1126/scisignal.adp5354

Andreas Papassotiropoulos, Dominique J.-F. de Quervain

引用次数: 0