Science Signaling最新文献_第4页

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

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: https://www.science.org/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":"https://www.science.org/doi/10.1126/scisignal.ade4335","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.ade4335","url":null,"abstract":"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.","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":"140586807","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

Lipid drops in on Alzheimer’s disease 脂质对老年痴呆症的影响

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: 10.1126/scisignal.adp4951

Amy E. Baek

引用次数: 0

Biasing microglia to help, not hurt 让小胶质细胞助人而非伤人

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: 10.1126/scisignal.adp3241

Leslie K. Ferrarelli

引用次数: 0

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice 小胶质细胞中的葡萄糖酰胺积累会引发 STING 依赖性神经炎症和小鼠神经退行性变

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: https://www.science.org/doi/10.1126/scisignal.adk8249

Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang

{"title":"Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice","authors":"Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang","doi":"https://www.science.org/doi/10.1126/scisignal.adk8249","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.adk8249","url":null,"abstract":"Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson’s disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586901","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