Science Signaling最新文献_第9页

Nude blebs expose cells to phagocytes 裸疵点使细胞暴露在吞噬细胞面前

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-30 DOI: 10.1126/scisignal.adq0353

Annalisa M. VanHook

引用次数: 0

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice 抑制 Hippo 通路激酶释放 WWC1，促进小鼠的 AMPAR 依赖性突触可塑性和长期记忆

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-30 DOI: 10.1126/scisignal.adj6603

Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Svenja Wiechmann, Silvia Martinelli, Kathrin Hafner, Tim Ebert, Ellen Junglas, Alexander S. Häusl, Max L. Pöhlmann, Mira Jakovcevski, Julius C. Pape, Anthony S. Zannas, Thomas Bajaj, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Christoph W. Turck, Jan M. Deussing, Gerhard Rammes, Andrew C. Robinson, Antony Payton, Michael C. Wehr, Valentin Stein, Christopher Murgatroyd, Joachim Kremerskothen, Bernhard Kuster, Carsten T. Wotjak, Nils C. Gassen

{"title":"Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice","authors":"Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Svenja Wiechmann, Silvia Martinelli, Kathrin Hafner, Tim Ebert, Ellen Junglas, Alexander S. Häusl, Max L. Pöhlmann, Mira Jakovcevski, Julius C. Pape, Anthony S. Zannas, Thomas Bajaj, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Christoph W. Turck, Jan M. Deussing, Gerhard Rammes, Andrew C. Robinson, Antony Payton, Michael C. Wehr, Valentin Stein, Christopher Murgatroyd, Joachim Kremerskothen, Bernhard Kuster, Carsten T. Wotjak, Nils C. Gassen","doi":"10.1126/scisignal.adj6603","DOIUrl":"10.1126/scisignal.adj6603","url":null,"abstract":"<div >The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 834","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819112","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

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":"17 833","pages":""},"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":"17 833","pages":""},"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":"17 832","pages":""},"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":"17 832","pages":""},"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":"17 831","pages":""},"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