Science Signaling最新文献_第5页

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-13 DOI: 10.1126/scisignal.ads1861

Annalisa M. VanHook

引用次数: 0

Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways AT1R C 端尾部的磷酸化模式指定了不同的下游信号通路。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-13 DOI: 10.1126/scisignal.adk5736

Clarice Gareri, Conrad T. Pfeiffer, Xue Jiang, Joao A. Paulo, Steven P. Gygi, Uyen Pham, Anand Chundi, Laura M. Wingler, Dean P. Staus, Tomasz Maciej Stepniewski, Jana Selent, Emilio Y. Lucero, Alyssa Grogan, Sudarshan Rajagopal, Howard A. Rockman

{"title":"Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways","authors":"Clarice Gareri, Conrad T. Pfeiffer, Xue Jiang, Joao A. Paulo, Steven P. Gygi, Uyen Pham, Anand Chundi, Laura M. Wingler, Dean P. Staus, Tomasz Maciej Stepniewski, Jana Selent, Emilio Y. Lucero, Alyssa Grogan, Sudarshan Rajagopal, Howard A. Rockman","doi":"10.1126/scisignal.adk5736","DOIUrl":"10.1126/scisignal.adk5736","url":null,"abstract":"<div >Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the “barcode” hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and β-arrestin recruitment, and for a synthetic biased agonist that only stimulates β-arrestin recruitment. The endogenous and β-arrestin–biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full β-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on β-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable β-arrestin–receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 849","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adk5736","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976968","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

Sleep to fight tumors 睡眠对抗肿瘤

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-06 DOI: 10.1126/scisignal.ads1573

Leslie K. Ferrarelli

引用次数: 0

Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons 与 ALS/FTD 基因 C9ORF72 相关的多聚-GR 重复序列会损害神经元的翻译延伸并诱发核糖毒性应激反应。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-06 DOI: 10.1126/scisignal.adl1030

Daoyuan Dong, Zhe Zhang, Yini Li, Malgorzata J. Latallo, Shaopeng Wang, Blake Nelson, Rong Wu, Gopinath Krishnan, Fen-Biao Gao, Bin Wu, Shuying Sun

{"title":"Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons","authors":"Daoyuan Dong, Zhe Zhang, Yini Li, Malgorzata J. Latallo, Shaopeng Wang, Blake Nelson, Rong Wu, Gopinath Krishnan, Fen-Biao Gao, Bin Wu, Shuying Sun","doi":"10.1126/scisignal.adl1030","DOIUrl":"10.1126/scisignal.adl1030","url":null,"abstract":"<div >Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR–induced toxicity and improved the survival of iPSC–derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 848","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898663","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 dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain 多巴胺能系统促进了大脑中肾素介导的淀粉样蛋白-β降解。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-06 DOI: 10.1126/scisignal.adk1822

Naoto Watamura, Naomasa Kakiya, Ryo Fujioka, Naoko Kamano, Mika Takahashi, Per Nilsson, Takashi Saito, Nobuhisa Iwata, Shigeyoshi Fujisawa, Takaomi C. Saido

{"title":"The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain","authors":"Naoto Watamura, Naomasa Kakiya, Ryo Fujioka, Naoko Kamano, Mika Takahashi, Per Nilsson, Takashi Saito, Nobuhisa Iwata, Shigeyoshi Fujisawa, Takaomi C. Saido","doi":"10.1126/scisignal.adk1822","DOIUrl":"10.1126/scisignal.adk1822","url":null,"abstract":"<div >Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer’s disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region–specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 848","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898665","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

Enhancing naloxone 加强纳洛酮。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-30 DOI: 10.1126/scisignal.adr9944

John F. Foley

引用次数: 0

Peripheral macrophages contribute to nociceptor priming in mice with chronic intermittent hypoxia 外周巨噬细胞有助于慢性间歇性缺氧小鼠的痛觉感受器启动。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-30 DOI: 10.1126/scisignal.adn8936

Samuel B. Chivers, Mary Ann Andrade, Robert J. Hammack, John Shannonhouse, Ruben Gomez, Yan Zhang, Brian Nguyen, Pankil Shah, Yu Shin Kim, Glenn M. Toney, Nathaniel A. Jeske

{"title":"Peripheral macrophages contribute to nociceptor priming in mice with chronic intermittent hypoxia","authors":"Samuel B. Chivers, Mary Ann Andrade, Robert J. Hammack, John Shannonhouse, Ruben Gomez, Yan Zhang, Brian Nguyen, Pankil Shah, Yu Shin Kim, Glenn M. Toney, Nathaniel A. Jeske","doi":"10.1126/scisignal.adn8936","DOIUrl":"10.1126/scisignal.adn8936","url":null,"abstract":"<div >Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is associated with increased incidence of chronic musculoskeletal pain. We investigated the mechanism of this association in a mouse model of chronic intermittent hypoxia (CIH) that mimics the repetitive hypoxemias of OSA. After 14 days of CIH, both male and female mice exhibited behaviors indicative of persistent pain, with biochemical markers in the spinal cord dorsal horn and sensory neurons of the dorsal root ganglia consistent with hyperalgesic priming. CIH, but not sleep fragmentation alone, induced an increase in macrophage recruitment to peripheral sensory tissues (sciatic nerve and dorsal root ganglia), an increase in inflammatory cytokines in the circulation, and nociceptor sensitization. Peripheral macrophage ablation blocked CIH-induced hyperalgesic priming. The findings suggest that correcting the hypoxia or targeting macrophage signaling might suppress persistent pain in patients with OSA.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 847","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adn8936","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856970","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 kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation 激酶 ITK 可控制 Ca2+ 介导的开关，从而平衡 TH17 和 Treg 细胞的分化。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-23 DOI: 10.1126/scisignal.adh2381

Orchi Anannya, Weishan Huang, Avery August

{"title":"The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation","authors":"Orchi Anannya, Weishan Huang, Avery August","doi":"10.1126/scisignal.adh2381","DOIUrl":"10.1126/scisignal.adh2381","url":null,"abstract":"<div >The balance of proinflammatory T helper type 17 (TH17) and anti-inflammatory T regulatory (Treg) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4+ T cells into TH17 and Treg cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2–inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca2+ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4+ T cells cultured under TH17-inducing conditions expressed the Treg transcription factor Foxp3 and did not develop into TH17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the Treg:TH17 ratio in the lung. These switched Foxp3+ Treg-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced Treg (iTreg) cells, but their chromatin accessibility profiles were intermediate between TH17 and iTreg cells. Like iTreg cells, switched Foxp3+ Treg-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the TH17 pioneer transcription factor BATF. This ITK-dependent switch between TH17 and Treg cells depended on Ca2+ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of TH17 and Treg cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 846","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753218","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

Generation of antitumor chimeric antigen receptors incorporating T cell signaling motifs 生成含有 T 细胞信号基团的抗肿瘤嵌合抗原受体。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-23 DOI: 10.1126/scisignal.adp8569

Lakshmi Balagopalan, Taylor Moreno, Haiying Qin, Benjamin C. Angeles, Taisuke Kondo, Jason Yi, Katherine M. McIntire, Neriah Alvinez, Sandeep Pallikkuth, Mariah E. Lee, Hidehiro Yamane, Andy D. Tran, Philippe Youkharibache, Raul E. Cachau, Naomi Taylor, Lawrence E. Samelson

{"title":"Generation of antitumor chimeric antigen receptors incorporating T cell signaling motifs","authors":"Lakshmi Balagopalan, Taylor Moreno, Haiying Qin, Benjamin C. Angeles, Taisuke Kondo, Jason Yi, Katherine M. McIntire, Neriah Alvinez, Sandeep Pallikkuth, Mariah E. Lee, Hidehiro Yamane, Andy D. Tran, Philippe Youkharibache, Raul E. Cachau, Naomi Taylor, Lawrence E. Samelson","doi":"10.1126/scisignal.adp8569","DOIUrl":"10.1126/scisignal.adp8569","url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 846","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753216","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

Ring around the mitochondria 环绕线粒体

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-07-23 DOI: 10.1126/scisignal.adr8314

Wei Wong

引用次数: 0