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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/15058


    Title: The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage
    Authors: Lin, YS;Chang, YC;Chao, TL;Tsai, YM;Jhuang, SJ;Ho, YH;Lai, TY;Liu, YL;Chen, CY;Tsai, CY;Hsueh, YP;Chang, SY;Chuang, TH;Lee, CY;Hsu, LC
    Contributors: Immunology Research Center
    Abstract: Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.
    Date: 2023-05-09
    Relation: Journal of Experimental Medicine. 2023 May 09;220(8):Article number e20220727.
    Link to: http://dx.doi.org/10.1084/jem.20220727
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1540-9538&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001006679100001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85159727903
    Appears in Collections:[莊宗顯] 期刊論文

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