ArticleThe Journal of experimental medicine2023
The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage.
Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 6 citations in OpenAlex.
- Zfand5 terminates TLR3/4 signaling and necroptosis by targeting TRIF to the proteasome for degradation.Cell death & disease · 2026Article
- ZNRF1 deficiency disrupts Fas ligand trafficking and immune balance.Cell death & disease · 2026Article
- Myeloid ZNRF1 suppresses autoimmune demyelination and neuroinflammation by regulating MHC-II-mediated T cell activation.Journal of neuroinflammation · 2025Article
- Article
- Involvement of nucleic acid-sensing toll-like receptors in human diseases and their controlling mechanisms.Journal of biomedical science · 2025Review
- Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.Nature communications · 2024Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.