The Src–ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage Article Swipe
You-Sheng Lin
,
Yung‐Chi Chang
,
Tai‐Ling Chao
,
Ya‐Min Tsai
,
Shu-Jhen Jhuang
,
Yu-Hsin Ho
,
Ting‐Yu Lai
,
Yiling Liu
,
Chiung-Ya Chen
,
Ching‐Yen Tsai
,
Yi‐Ping Hsueh
,
Sui‐Yuan Chang
,
Tsung‐Hsien Chuang
,
Chih‐Yuan Lee
,
Li‐Chung Hsu
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1084/jem.20220727
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1084/jem.20220727
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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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1084/jem.20220727
- OA Status
- hybrid
- Cited By
- 5
- References
- 70
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4375954798
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4375954798Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1084/jem.20220727Digital Object Identifier
- Title
-
The Src–ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damageWork title
- Type
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articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
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2023Year of publication
- Publication date
-
2023-05-09Full publication date if available
- Authors
-
You-Sheng Lin, Yung‐Chi Chang, Tai‐Ling Chao, Ya‐Min Tsai, Shu-Jhen Jhuang, Yu-Hsin Ho, Ting‐Yu Lai, Yiling Liu, Chiung-Ya Chen, Ching‐Yen Tsai, Yi‐Ping Hsueh, Sui‐Yuan Chang, Tsung‐Hsien Chuang, Chih‐Yuan Lee, Li‐Chung HsuList of authors in order
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https://doi.org/10.1084/jem.20220727Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
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hybridOpen access status per OpenAlex
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https://doi.org/10.1084/jem.20220727Direct OA link when available
- Concepts
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TLR3, Interferon, Cell biology, Biology, Signal transduction, Innate immune system, Proto-oncogene tyrosine-protein kinase Src, Ubiquitin, Immune system, Immunology, Toll-like receptor, Biochemistry, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
5Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 4, 2024: 1Per-year citation counts (last 5 years)
- References (count)
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70Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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