The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage
Journal
The Journal of experimental medicine
Journal Volume
220
Journal Issue
8
Date Issued
2023-08-07
Author(s)
Lin, You-Sheng
Chang, Yung-Chi
Tsai, Ya-Min
Jhuang, Shu-Jhen
Ho, Yu-Hsin
Lai, Ting-Yu
Liu, Yi-Ling
Chen, Chiung-Ya
Tsai, Ching-Yen
Hsueh, Yi-Ping
Chuang, Tsung-Hsien
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.
Type
journal article