https://scholars.lib.ntu.edu.tw/handle/123456789/634492
標題: | The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage | 作者: | Lin, You-Sheng Chang, Yung-Chi TAI-LING CHAO Tsai, Ya-Min Jhuang, Shu-Jhen Ho, Yu-Hsin Lai, Ting-Yu Liu, Yi-Ling Chen, Chiung-Ya Tsai, Ching-Yen Hsueh, Yi-Ping SUI-YUAN CHANG Chuang, Tsung-Hsien CHIH-YUAN LEE LI-CHUNG HSU |
公開日期: | 7-八月-2023 | 卷: | 220 | 期: | 8 | 來源出版物: | The Journal of experimental medicine | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/634492 | ISSN: | 0022-1007 1540-9538 |
DOI: | 10.1084/jem.20220727 |
顯示於: | 醫學檢驗暨生物技術學系 |
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