Science Signaling最新文献

Poor sleep for pass-out drunks

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-04-01 DOI: 10.1126/scisignal.adx7187

Annalisa M. VanHook

引用次数: 0

RIPK3 coordinates RHIM domain–dependent antiviral inflammatory transcription in neurons

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-04-01 DOI: 10.1126/scisignal.ado9745

Sigal B. Kofman, Lan H. Chu, Joshua M. Ames, Suny Dayane Chavarria, Katrina Lichauco, Brian P. Daniels, Andrew Oberst

{"title":"RIPK3 coordinates RHIM domain–dependent antiviral inflammatory transcription in neurons","authors":"Sigal B. Kofman, Lan H. Chu, Joshua M. Ames, Suny Dayane Chavarria, Katrina Lichauco, Brian P. Daniels, Andrew Oberst","doi":"10.1126/scisignal.ado9745","DOIUrl":"10.1126/scisignal.ado9745","url":null,"abstract":"<div >Neurons are postmitotic, nonregenerative cells that have evolved fine-tuned immunological responses to maintain life-long cellular integrity, including resistance to common programmed cell death pathways such as necroptosis. We previously demonstrated a necroptosis-independent role for the key necroptotic kinase RIPK3 in host defense against neurotropic flavivirus infection. Here, we show that RIPK3 activation had distinct outcomes in primary cortical neurons when compared with mouse embryonic fibroblasts (MEFs) during Zika virus (ZIKV) infection or after sterile activation. We found that RIPK3 activation did not induce neuronal death but instead drove antiviral gene transcription after ZIKV infection. Although RIPK3 activation in MEFs induced cell death, ablation of downstream cell death effectors unveiled a RIPK3-dependent transcriptional program that largely overlapped with that observed in ZIKV-infected neurons. In death-resistant MEFs, RIPK3-dependent transcription relied on interactions with the RHIM domain–containing proteins RIPK1 and TRIF, similar to the requirements for the RIPK3-dependent antiviral transcriptional signature in ZIKV-infected neurons. These findings suggest that the pleotropic functions of RIPK3 are largely context dependent and that in cells that are resistant to cell death, RIPK3 acts as a mediator of inflammatory transcription.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 880","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750034","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

A sensitive biosensor of endogenous Gαi activity enables the accurate characterization of endogenous GPCR agonist responses

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-25 DOI: 10.1126/scisignal.adp6457

Alex Luebbers, Remi Janicot, Jingyi Zhao, Clementine E. Philibert, Mikel Garcia-Marcos

{"title":"A sensitive biosensor of endogenous Gαi activity enables the accurate characterization of endogenous GPCR agonist responses","authors":"Alex Luebbers, Remi Janicot, Jingyi Zhao, Clementine E. Philibert, Mikel Garcia-Marcos","doi":"10.1126/scisignal.adp6457","DOIUrl":"10.1126/scisignal.adp6457","url":null,"abstract":"<div >The activation of heterotrimeric G proteins (Gαβγ) by G protein–coupled receptors (GPCRs) is a mechanism broadly used by eukaryotes to transduce signals across the plasma membrane and a target for many clinical drugs. Many optical biosensors commonly used for measuring GPCR-stimulated G protein activity rely on exogenously expressed GPCRs and/or G proteins, which compromise readout fidelity. Biosensors that measure endogenous signaling may interfere with the signaling process under investigation or have a limited dynamic range of detection, hindering applicability. Here, we developed an optical BRET-based biosensor, Gα<sub>i</sub> bONE-GO, that detects endogenous GTP-bound (active) Gα<sub>i</sub> upon stimulation of endogenous GPCRs more robustly than existing sensors of endogenous activity. Its design leverages the Gα<sub>i</sub>-binding protein GINIP as a high-affinity and specific detector of Gα<sub>i</sub>-GTP. We optimized this design to prevent interference with downstream G<sub>i</sub>-dependent signaling and to enable implementation in different experimental systems having endogenous GPCRs, including adenosine receptors in primary astroglial cells and opioid receptors in cell lines. In a neuronal cell line, Gα<sub>i</sub> bONE-GO revealed activation profiles indicating that several natural opioid neuropeptides acted as partial agonists, in contrast with their characterization as full agonists using biosensors that depend on exogenously expressed receptors and G proteins. The Gα<sub>i</sub> bONE-GO biosensor is a direct and sensitive detector of endogenous activation of Gα<sub>i</sub> proteins by GPCRs in different experimental settings but does not interfere with the subsequent propagation of signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 879","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707717","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

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-25 DOI: 10.1126/scisignal.adk3320

Xiaoyong Chen, Xiangjun Tang, Ying Xie, Benedette J. Cuffari, Caroline Tang, Fei Cao, Xingchun Gao, Zhouqi Meng, Philip W. Noble, Melissa R. Young, Olivia M. Turk, Anupama Shirali, Joseph Gera, Robert N. Nishimura, Jiangbing Zhou, James E. Hansen

{"title":"A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells","authors":"Xiaoyong Chen, Xiangjun Tang, Ying Xie, Benedette J. Cuffari, Caroline Tang, Fei Cao, Xingchun Gao, Zhouqi Meng, Philip W. Noble, Melissa R. Young, Olivia M. Turk, Anupama Shirali, Joseph Gera, Robert N. Nishimura, Jiangbing Zhou, James E. Hansen","doi":"10.1126/scisignal.adk3320","DOIUrl":"10.1126/scisignal.adk3320","url":null,"abstract":"<div >Nucleic acid–mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody–nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 879","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707719","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

Treating neuroinflammation through the nose

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-25 DOI: 10.1126/scisignal.adx5434

Leslie K. Ferrarelli

引用次数: 0

Structural analysis reveals how tetrameric tyrosine-phosphorylated STAT1 is targeted by the rabies virus P-protein

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-18 DOI: 10.1126/scisignal.ads2210

Aoi Sugiyama, Miku Minami, Kaito Ugajin, Satomi Inaba-Inoue, Nana Yabuno, Yuichiro Takekawa, Sun Xiaomei, Shiho Takei, Mina Sasaki, Tomo Nomai, Xinxin Jiang, Shunsuke Kita, Katsumi Maenaka, Mika Hirose, Min Yao, Paul R. Gooley, Gregory W. Moseley, Yukihiko Sugita, Toyoyuki Ose

{"title":"Structural analysis reveals how tetrameric tyrosine-phosphorylated STAT1 is targeted by the rabies virus P-protein","authors":"Aoi Sugiyama, Miku Minami, Kaito Ugajin, Satomi Inaba-Inoue, Nana Yabuno, Yuichiro Takekawa, Sun Xiaomei, Shiho Takei, Mina Sasaki, Tomo Nomai, Xinxin Jiang, Shunsuke Kita, Katsumi Maenaka, Mika Hirose, Min Yao, Paul R. Gooley, Gregory W. Moseley, Yukihiko Sugita, Toyoyuki Ose","doi":"10.1126/scisignal.ads2210","DOIUrl":"10.1126/scisignal.ads2210","url":null,"abstract":"<div >Signal transducer and activator of transcription (STAT) family members mediate signaling in the Janus kinase (JAK)–STAT pathway and are activated by phosphorylation at a conserved tyrosine residue, resulting in dimerization through reciprocal interactions between the phosphotyrosine and a Src homology 2 (SH2) domain. Tyrosine-phosphorylated STAT (pY-STAT) then translocates to the nucleus to induce the expression of genes encoding antiviral proteins. Although the active and functional forms of STATs are conventionally considered to be dimers, STATs can undergo higher-order oligomerization, which is implicated in regulating transcriptional activity. We present the cryo–electron microscopy (cryo-EM) structure of the tetrameric form of intact pY-STAT1 in complex with DNA, which indicates that interactions between the amino-terminal domains (NTDs) of STAT1 induce oligomerization. The tetrameric structure revealed a compact conformation with a previously uncharacterized binding interface: Two DNA-bound dimers are twofold symmetrically aligned to transform into a tandem DNA-binding model without NTD dimer separation. Moreover, biochemical analyses indicated that the rabies virus P-protein selectively targeted tetrameric pY-STAT1. Combined with data showing which regions contribute to the interaction between pY-STAT1 and the P-protein, we constructed a binding model explaining how P recognizes the pY-STAT1 tetramer. These data provide insight into how pathogenic viruses target signaling pathways that mediate the host immune response.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 878","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655431","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

Tales from the cryptic pocket 来自神秘口袋的故事

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-18 DOI: 10.1126/scisignal.adx4130

John F. Foley

引用次数: 0

The kinase PLK1 promotes Hedgehog signaling–dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-18 DOI: 10.1126/scisignal.adi5174

Qiongsi Zhang, Jia Peng, Yanquan Zhang, Jinghui Liu, Daheng He, Yue Zhao, Xinyi Wang, Chaohao Li, Yifan Kong, Ruixin Wang, Fengyi Mao, Chi Wang, Qing Wang, Min Zhang, Jianlin Wang, Hsin-Sheng Yang, Xiaoqi Liu

{"title":"The kinase PLK1 promotes Hedgehog signaling–dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer","authors":"Qiongsi Zhang, Jia Peng, Yanquan Zhang, Jinghui Liu, Daheng He, Yue Zhao, Xinyi Wang, Chaohao Li, Yifan Kong, Ruixin Wang, Fengyi Mao, Chi Wang, Qing Wang, Min Zhang, Jianlin Wang, Hsin-Sheng Yang, Xiaoqi Liu","doi":"10.1126/scisignal.adi5174","DOIUrl":"10.1126/scisignal.adi5174","url":null,"abstract":"<div >Enzalutamide, a second-generation androgen receptor inhibitor (also known as an antiandrogen), is used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Tumors often acquire resistance to enzalutamide. Tumor progression and enzalutamide resistance are associated with decreased abundance of the tumor suppressor PDCD4. In normal dividing cells, PDCD4 abundance is low when that of the kinase PLK1 is high. In this study, we found that PLK1 acted on PDCD4 to promote enzalutamide resistance in CRPC cells in culture and in mice via a mechanism that revealed an effective combination therapy. PLK1 phosphorylated PDCD4 at Ser<sup>239</sup>, leading to its degradation and consequently inducing the transcriptional activation of Hedgehog (Hh) signaling by c-MYC. Hh signaling supports tumor cell proliferation and stemness by inducing the enzyme UDP-glucuronosyltransferase 2B15 (UGT2B15), which promotes the metabolic clearance of drugs and steroid hormones. Thus, this pathway may circumvent androgen receptor dependence, thereby reducing cellular sensitivity to enzalutamide. Knocking down UGT2B15 enhanced enzalutamide-induced cell apoptosis and growth arrest in a PDCD4-dependent manner. Combining enzalutamide with the clinically approved Hh pathway inhibitor vismodegib inhibited cell growth and promoted apoptosis in enzalutamide-resistant cell cultures and xenografts in vivo. Our findings reveal a mechanism of PLK1-mediated enzalutamide resistance and suggest a potential therapeutic strategy to overcome this resistance in prostate cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 878","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adi5174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655433","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

Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen

{"title":"Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function","authors":"Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen","doi":"","DOIUrl":"","url":null,"abstract":"<div >Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6<i></i>) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6<i></i> deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6<i></i> deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure–induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6<i></i> deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 877","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595749","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

NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage NEMO 对引导激酶 IKKα 和 ATM 到达 DNA 损伤部位至关重要

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Josune Alonso-Marañón, Laura Solé, Daniel Álvarez-Villanueva, María Maqueda, Teresa Lobo-Jarne, Ángela Montoto, Jose Yélamos, Eva Borràs, Leire Uraga, Christopher Hooper, Eduard Sabidó, Shigeki Miyamoto, Anna Bigas, Lluís Espinosa

{"title":"NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage","authors":"Josune Alonso-Marañón, Laura Solé, Daniel Álvarez-Villanueva, María Maqueda, Teresa Lobo-Jarne, Ángela Montoto, Jose Yélamos, Eva Borràs, Leire Uraga, Christopher Hooper, Eduard Sabidó, Shigeki Miyamoto, Anna Bigas, Lluís Espinosa","doi":"","DOIUrl":"","url":null,"abstract":"<div >The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα. Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKKα complex, which was required to target active ATM and IKKα to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKKα-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKKα. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKKα, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 877","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595746","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