Science Signaling最新文献_第4页

The biology of addiction

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-02-04

Eric J. Nestler

引用次数: 0

Antigen receptor ITAMs provide tonic signaling by acting as guanine nucleotide exchange factors to directly activate R-RAS2

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-28 DOI: 10.1126/scisignal.adk4204

Alejandro M. Hortal, Enrique Calleja, Clara L. Oeste, Irene Arellano, Marta Lacuna, Soledad Blanco, Nadia Martín-Blanco, Inmaculada Montanuy, Antonio Alcamí, Xosé R. Bustelo, Balbino Alarcón

{"title":"Antigen receptor ITAMs provide tonic signaling by acting as guanine nucleotide exchange factors to directly activate R-RAS2","authors":"Alejandro M. Hortal, Enrique Calleja, Clara L. Oeste, Irene Arellano, Marta Lacuna, Soledad Blanco, Nadia Martín-Blanco, Inmaculada Montanuy, Antonio Alcamí, Xosé R. Bustelo, Balbino Alarcón","doi":"10.1126/scisignal.adk4204","DOIUrl":"10.1126/scisignal.adk4204","url":null,"abstract":"<div >The small GTPase R-RAS2 regulates homeostatic proliferation and survival of T and B lymphocytes and, when present in high amounts, drives the development of B cell chronic lymphocytic leukemia. In normal and leukemic lymphocytes, R-RAS2 constitutively binds to antigen receptors through their immunoreceptor tyrosine-based activation motifs (ITAMs) and promotes tonic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Here, we examined the molecular mechanisms underlying this direct interaction and its consequences for R-RAS2 activity. R-RAS2 exhibited direct, high-affinity interactions with ITAM peptides derived from B and T cell receptors through a proline-rich sequence in the hypervariable domain of R-RAS2. In resting T and B cells, the presence of antigen receptors at the plasma membrane was sufficient to promote the activation of R-RAS2 and PI3K, and mutations that abolished the interaction of R-RAS2 with ITAMs reduced R-RAS2 signaling. Binding to ITAMs increased GDP-GTP exchange on R-RAS2 through a mechanism distinct from that by which conventional cytosolic guanosine nucleotide exchange factors (GEFs) activate RAS proteins. These results define antigen receptors as noncanonical GEFs involved in the basal activation state of R-RAS2 in lymphocytes. Such a mechanism may underlie the leukemic transformation of B cells that occurs when wild-type R-RAS2 is present in high amounts.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 871","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061292","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

Alarmin’ lymphoid developments

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-28 DOI: 10.1126/scisignal.adw1930

Amy E. Baek

引用次数: 0

HIV-1 Vpu and SARS-CoV-2 ORF3a proteins disrupt STING-mediated activation of antiviral NF-κB signaling

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-21 DOI: 10.1126/scisignal.add6593

Yajuan Rui, Si Shen, Yanpu Wang, Leyi Cheng, Shiqi Chen, Ying Hu, Yong Cai, Wei Wei, Jiaming Su, Xiao-Fang Yu

{"title":"HIV-1 Vpu and SARS-CoV-2 ORF3a proteins disrupt STING-mediated activation of antiviral NF-κB signaling","authors":"Yajuan Rui, Si Shen, Yanpu Wang, Leyi Cheng, Shiqi Chen, Ying Hu, Yong Cai, Wei Wei, Jiaming Su, Xiao-Fang Yu","doi":"10.1126/scisignal.add6593","DOIUrl":"10.1126/scisignal.add6593","url":null,"abstract":"<div >Activation of the stimulator of interferon genes (STING) pathway by cytosolic DNA leads to the activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Although many viruses produce proteins that inhibit IRF3-dependent antiviral responses, some viruses produce proteins that inhibit STING-induced NF-κB activation without blocking IRF3 activation. Here, we found that STING-activated, NF-κB–dependent, and IRF3-independent innate immunity inhibited the replication of the DNA virus herpes simplex virus type 1 (HSV-1), the RNA virus coxsackievirus A16 (CV-A16), and the retrovirus HIV-1. The HIV-1 nonstructural protein Vpu bound to STING and prevented it from interacting with the upstream NF-κB pathway kinase inhibitor of NF-κB subunit β (IKKβ), thus blocking NF-κB signaling. This function of Vpu was conserved among Vpu proteins from diverse HIV-1 and simian immunodeficiency virus strains and was distinct from its action in disrupting other host antiviral pathways. Furthermore, the ORF3a protein from the coronavirus SARS-CoV-2 also promoted viral replication by interacting with STING and blocking STING-induced activity of NF-κB but not of IRF3. These findings demonstrate that diverse viral proteins have convergently evolved to selectively inhibit NF-κB–mediated innate immunity downstream of STING activation, suggesting that targeting this pathway may represent a promising antiviral strategy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 870","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061278","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

Biotin mitigates the development of manganese-induced, Parkinson’s disease–related neurotoxicity in Drosophila and human neurons

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-21 DOI: 10.1126/scisignal.adn9868

Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W. Miller, Souvarish Sarkar

{"title":"Biotin mitigates the development of manganese-induced, Parkinson’s disease–related neurotoxicity in Drosophila and human neurons","authors":"Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W. Miller, Souvarish Sarkar","doi":"10.1126/scisignal.adn9868","DOIUrl":"10.1126/scisignal.adn9868","url":null,"abstract":"<div >Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson’s disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult <i>Drosophila</i> model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B<sub>7</sub>) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 870","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061277","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

Bypassing senescence 绕过衰老。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-21 DOI: 10.1126/scisignal.adv9441

Annalisa M. VanHook

引用次数: 0

Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines 淋巴细胞系BTK信号膜结合模块二聚化的条件要求。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-14 DOI: 10.1126/scisignal.ado1252

Timothy J. Eisen, Sam Ghaffari-Kashani, Chien-Lun Hung, Jay T. Groves, Arthur Weiss, John Kuriyan

{"title":"Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines","authors":"Timothy J. Eisen, Sam Ghaffari-Kashani, Chien-Lun Hung, Jay T. Groves, Arthur Weiss, John Kuriyan","doi":"10.1126/scisignal.ado1252","DOIUrl":"10.1126/scisignal.ado1252","url":null,"abstract":"<div >Bruton’s tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin homology and tec homology (PH-TH) domains of BTK are required for signaling. Dimerization of the PH-TH module strongly stimulates the kinase activity of BTK in vitro. Here, we investigated whether BTK dimerizes in cells using the PH-TH module and whether this dimerization is necessary for signaling. To address this question, we developed high-throughput mutagenesis assays for BTK function in Ramos B cells and Jurkat T cells. We measured the fitness costs for thousands of point mutations in the PH-TH module and kinase domain to assess whether dimerization of the PH-TH module and BTK kinase activity were necessary for function. In Ramos cells, we found that neither PH-TH dimerization nor kinase activity was required for BTK signaling. Instead, in Ramos cells, BTK signaling was enhanced by PH-TH module mutations that increased membrane adsorption, even at the cost of reduced PH-TH dimerization. In contrast, in Jurkat cells, we found that BTK signaling depended on both PH-TH dimerization and kinase activity. Evolutionary analysis indicated that BTK proteins in organisms that evolved before the divergence of ray-finned fishes lacked PH-TH dimerization but had active kinase domains, similar to other Tec family kinases. Thus, PH-TH dimerization is a distinct feature of BTK that evolved to exert stricter regulatory control on kinase activity as adaptive immune systems gained increased complexity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 869","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985247","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

HSV and a tale of two taus HSV和双关语。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-14 DOI: 10.1126/scisignal.adv8245

Leslie K. Ferrarelli

引用次数: 0

Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model 在人脑组织模型中，重复性损伤通过重新激活HSV-1诱导与阿尔茨海默病相关的表型。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado6430

Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, Marilyn Kelly, Ruth F. Itzhaki, David L. Kaplan

{"title":"Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model","authors":"Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, Marilyn Kelly, Ruth F. Itzhaki, David L. Kaplan","doi":"10.1126/scisignal.ado6430","DOIUrl":"10.1126/scisignal.ado6430","url":null,"abstract":"<div >Infection with herpes simplex virus type 1 (HSV-1) in the brains of <i>APOE4</i> carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of <i>APOE4</i>-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 868","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957822","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

IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages IRF1与ISGF3或GAF协同在巨噬细胞中形成先天免疫新生增强因子。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado8860

Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J. Cheng, Alexander Hoffmann

{"title":"IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages","authors":"Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J. Cheng, Alexander Hoffmann","doi":"10.1126/scisignal.ado8860","DOIUrl":"10.1126/scisignal.ado8860","url":null,"abstract":"<div >Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)–induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because <i>IRF1</i> expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce <i>IRF1</i> expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ–secreting T cells but not bystander macrophages exposed transiently to type I IFN.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 868","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957821","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