Science Signaling最新文献_第3页

TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis TNF-α 通过 ITK-Akt-mTOR 信号驱动 CD4+ T 细胞代谢重编程，类风湿性关节炎患者的代谢重编程失调

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-23 DOI: 10.1126/scisignal.adg5678

Emma L. Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A. Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe

{"title":"TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis","authors":"Emma L. Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A. Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe","doi":"10.1126/scisignal.adg5678","DOIUrl":"10.1126/scisignal.adg5678","url":null,"abstract":"<div >Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor–α (TNF-α) released by human naïve CD4<sup>+</sup> T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (T<sub>H</sub>1) and T<sub>H</sub>17 cells, but not that of regulatory T cells. CD4<sup>+</sup> T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell–derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140639688","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

Glia are powerhouses for sleep 神经胶质细胞是睡眠的动力源泉

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-23 DOI: 10.1126/scisignal.adp9115

Leslie K. Ferrarelli

引用次数: 0

Optogenetically controlled inflammasome activation demonstrates two phases of cell swelling during pyroptosis 光遗传学控制的炎症小体激活显示了热核病过程中细胞肿胀的两个阶段

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-23 DOI: 10.1126/scisignal.abn8003

Julien Nadjar, Sylvain Monnier, Estelle Bastien, Anne-Laure Huber, Christiane Oddou, Léa Bardoulet, Hubert B. Leloup, Gabriel Ichim, Christophe Vanbelle, Bénédicte F. Py, Olivier Destaing, Virginie Petrilli

{"title":"Optogenetically controlled inflammasome activation demonstrates two phases of cell swelling during pyroptosis","authors":"Julien Nadjar, Sylvain Monnier, Estelle Bastien, Anne-Laure Huber, Christiane Oddou, Léa Bardoulet, Hubert B. Leloup, Gabriel Ichim, Christophe Vanbelle, Bénédicte F. Py, Olivier Destaing, Virginie Petrilli","doi":"10.1126/scisignal.abn8003","DOIUrl":"10.1126/scisignal.abn8003","url":null,"abstract":"<div >Inflammasomes are multiprotein platforms that control caspase-1 activation, which process the inactive precursor forms of the inflammatory cytokines IL-1β and IL-18, leading to an inflammatory type of programmed cell death called pyroptosis. Studying inflammasome-driven processes, such as pyroptosis-induced cell swelling, under controlled conditions remains challenging because the signals that activate pyroptosis also stimulate other signaling pathways. We designed an optogenetic approach using a photo-oligomerizable inflammasome core adapter protein, apoptosis-associated speck–like containing a caspase recruitment domain (ASC), to temporally and quantitatively manipulate inflammasome activation. We demonstrated that inducing the light-sensitive oligomerization of ASC was sufficient to recapitulate the classical features of inflammasomes within minutes. This system showed that there were two phases of cell swelling during pyroptosis. This approach offers avenues for biophysical investigations into the intricate nature of cellular volume control and plasma membrane rupture during cell death.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140639690","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

EGFR-dependent endocytosis of Wnt9a and Fzd9b promotes β-catenin signaling during hematopoietic stem cell development in zebrafish 在斑马鱼造血干细胞发育过程中，表皮生长因子受体依赖性内吞 Wnt9a 和 Fzd9b，促进β-catenin 信号传导

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adf4299

Nicole Nguyen, Kelsey A. Carpenter, Jessica Ensing, Carla Gilliland, Emma J. Rudisel, Emily M. Mu, Kate E. Thurlow, Timothy J. Triche Jr., Stephanie Grainger

{"title":"EGFR-dependent endocytosis of Wnt9a and Fzd9b promotes β-catenin signaling during hematopoietic stem cell development in zebrafish","authors":"Nicole Nguyen, Kelsey A. Carpenter, Jessica Ensing, Carla Gilliland, Emma J. Rudisel, Emily M. Mu, Kate E. Thurlow, Timothy J. Triche Jr., Stephanie Grainger","doi":"10.1126/scisignal.adf4299","DOIUrl":"10.1126/scisignal.adf4299","url":null,"abstract":"<div >Cell-to-cell communication through secreted Wnt ligands that bind to members of the Frizzled (Fzd) family of transmembrane receptors is critical for development and homeostasis. Wnt9a signals through Fzd9b, the co-receptor LRP5 or LRP6 (LRP5/6), and the epidermal growth factor receptor (EGFR) to promote early proliferation of zebrafish and human hematopoietic stem cells during development. Here, we developed fluorescently labeled, biologically active Wnt9a and Fzd9b fusion proteins to demonstrate that EGFR-dependent endocytosis of the ligand-receptor complex was required for signaling. In human cells, the Wnt9a-Fzd9b complex was rapidly endocytosed and trafficked through early and late endosomes, lysosomes, and the endoplasmic reticulum. Using small-molecule inhibitors and genetic and knockdown approaches, we found that Wnt9a-Fzd9b endocytosis required EGFR-mediated phosphorylation of the Fzd9b tail, caveolin, and the scaffolding protein EGFR protein substrate 15 (EPS15). LRP5/6 and the downstream signaling component AXIN were required for Wnt9a-Fzd9b signaling but not for endocytosis. Knockdown or loss of EPS15 impaired hematopoietic stem cell development in zebrafish. Other Wnt ligands do not require endocytosis for signaling activity, implying that specific modes of endocytosis and trafficking may represent a method by which Wnt-Fzd specificity is established.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559887","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

Taking down tumors takes atypical integrins 攻克肿瘤需要非典型整合素

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adp7684

John F. Foley

引用次数: 0

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens 解码可卡因诱导的小鼠脑核蛋白质组适应性变化

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adl4738

Philipp Mews, Lucas Sosnick, Ashik Gurung, Simone Sidoli, Eric J. Nestler

{"title":"Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens","authors":"Philipp Mews, Lucas Sosnick, Ashik Gurung, Simone Sidoli, Eric J. Nestler","doi":"10.1126/scisignal.adl4738","DOIUrl":"10.1126/scisignal.adl4738","url":null,"abstract":"<div >Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140559885","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

Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection Miz1 在甲型流感病毒感染过程中抑制 I 型干扰素的产生并限制病毒的清除

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adg7867

Wenjiao Wu, Vinothini Arunagiri, Hanh Chi Do-Umehara, Cong Chen, Shuyin Gu, Indrani Biswas, Karen M. Ridge, G. R. Scott Budinger, Shuwen Liu, Jing Liu

{"title":"Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection","authors":"Wenjiao Wu, Vinothini Arunagiri, Hanh Chi Do-Umehara, Cong Chen, Shuyin Gu, Indrani Biswas, Karen M. Ridge, G. R. Scott Budinger, Shuwen Liu, Jing Liu","doi":"10.1126/scisignal.adg7867","DOIUrl":"10.1126/scisignal.adg7867","url":null,"abstract":"<div >Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of <i>Ifna</i> and <i>Ifnb</i>. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)–mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541210","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

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":null,"pages":null},"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":null,"pages":null},"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