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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\u2212\/\u2212 mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src\u2013ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.<\/jats:p>","DOI":"10.1084\/jem.20220727","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T02:21:02Z","timestamp":1677810062000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["The Src\u2013ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6895-4925","authenticated-orcid":true,"given":"You-Sheng","family":"Lin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bqach95","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Medicine, College of Medicine, National Taiwan University 1 , Taipei, 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