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Tytuł:
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β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion.
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Autorzy:
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Zhang Y; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Li M; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Li L; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Qian G; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Wang Y; Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Army Medical University, Chongqing, 400038, China.
Chen Z; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Liu J; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Fang C; Department of Vascular Surgery, Zhongshan Hospital Affiliated to Fudan University, Institute of Vascular Surgery, Fudan University, Shanghai, 200032, China.
Huang F; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, China.
Guo D; Department of Vascular Surgery, Zhongshan Hospital Affiliated to Fudan University, Institute of Vascular Surgery, Fudan University, Shanghai, 200032, China.
Zou Q; Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Army Medical University, Chongqing, 400038, China.
Chu Y; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China.
Yan D; Department of Immunology, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, 200032, China. .
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Źródło:
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Nature communications [Nat Commun] 2020 Nov 26; Vol. 11 (1), pp. 6000. Date of Electronic Publication: 2020 Nov 26.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : Nature Pub. Group
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MeSH Terms:
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Carvedilol/*pharmacology
Immune Evasion/*immunology
Membrane Proteins/*metabolism
Nucleotidyltransferases/*metabolism
Virus Diseases/*immunology
beta-Arrestin 2/*metabolism
Animals ; Carvedilol/therapeutic use ; Disease Models, Animal ; Drug Repositioning ; HEK293 Cells ; Herpesvirus 1, Human/immunology ; Humans ; Immune Evasion/drug effects ; Interferon-beta/metabolism ; Macrophages, Peritoneal/immunology ; Macrophages, Peritoneal/metabolism ; Male ; Mice ; Primary Cell Culture ; Proteolysis/drug effects ; RAW 264.7 Cells ; RNA-Seq ; Sendai virus/immunology ; Signal Transduction/drug effects ; Signal Transduction/immunology ; Vesiculovirus/immunology ; Virus Diseases/drug therapy ; Virus Diseases/virology ; beta-Arrestin 2/agonists ; beta-Arrestin 2/genetics
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Substance Nomenclature:
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0 (Arrb2 protein, mouse)
0 (Membrane Proteins)
0 (Sting1 protein, mouse)
0 (beta-Arrestin 2)
0K47UL67F2 (Carvedilol)
77238-31-4 (Interferon-beta)
EC 2.7.7.- (Nucleotidyltransferases)
EC 2.7.7.- (cGAS protein, mouse)
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Entry Date(s):
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Date Created: 20201127 Date Completed: 20201211 Latest Revision: 20201214
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Update Code:
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20240105
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PubMed Central ID:
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PMC7691508
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DOI:
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10.1038/s41467-020-19849-9
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PMID:
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33243993
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Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS-STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.