Institute of Molecular Medicine, College of Medicine, National Taiwan University , Taipei, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Exp Med. 2023 Aug 7;220(8). doi: 10.1084/jem.20220727. Epub 2023 May 9.
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.
I 型干扰素是重要的抗病毒细胞因子，但干扰素的过度产生对宿主有害。TLR3 驱动的免疫反应对哺乳动物抗病毒免疫至关重要，其细胞内定位决定了 I 型干扰素的诱导；然而，终止 TLR3 信号的机制仍不清楚。在这里，我们表明 E3 泛素连接酶 ZNRF1 控制 TLR3 分拣到多泡体/溶酶体中，以终止信号和 I 型干扰素的产生。在机制上，TLR3 结合激活的 c-Src 激酶在酪氨酸 103 处磷酸化 ZNRF1，介导 TLR3 在赖氨酸 813 处的 K63 连接泛素化，并促进 TLR3 溶酶体运输和降解。由于 I 型干扰素产生增强，ZNRF1 缺陷型小鼠和细胞对脑心肌炎病毒和 SARS-CoV-2 的感染具有抗性。然而，由于抗病毒免疫触发的肺屏障损伤加剧，Znrf1-/- 小鼠对呼吸道细菌的二次感染易感性增强。我们的研究强调了 c-Src-ZNRF1 轴作为控制 TLR3 运输和终止 TLR3 信号的负反馈机制。
