| First Author | Lin YS | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 8 | PubMed ID | 37158982 |
| Mgi Jnum | J:335622 | Mgi Id | MGI:7481880 |
| Doi | 10.1084/jem.20220727 | Citation | Lin YS, et al. (2023) The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage. J Exp Med 220(8) |
| abstractText | 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. |
