Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Cell Rep. 2019 Oct 29;29(5):1249-1260.e4. doi: 10.1016/j.celrep.2019.09.069.
γ-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here, we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting the E3 ligase TRIM21. The 1-pyrin region of IFI16 is responsible for the IFI16-STING interaction, and the first three lysines in the N-terminal region of IFI16 are the key sites that lead to STING-mediated IFI16 ubiquitination and degradation. Compared to wild-type IFI16, a higher level of viral DNA triggered IFN-β and antiviral IFN-stimulated gene expression, and thus less HSV-1 infection, was observed in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant that is resistant to degradation. STING-mediated negative feedback regulation of IFI16 restricts IFN-I overproduction during antiviral immunity to avoid autoimmune diseases.
γ-干扰素诱导蛋白 16（IFI16）是一种关键的 DNA 传感器，可触发下游 STING 依赖性 I 型干扰素（IFN-I）的产生和抗病毒免疫。然而，目前尚不清楚如何负调控 IFI16 以避免 IFN-I 的过度产生和自身免疫。在这里，我们发现 STING 可直接与 IFI16 相互作用，并通过募集 E3 连接酶 TRIM21 通过泛素-蛋白酶体途径促进 IFI16 的降解。IFI16 的 1-吡喃区域负责 IFI16-STING 相互作用，而 IFI16 氨基末端区域的前三个赖氨酸是导致 STING 介导的 IFI16 泛素化和降解的关键位点。与野生型 IFI16 相比，在转染了 IFI16-K3/4/6R（一种不易降解的 IFI16 突变体）的细胞中，更高水平的病毒 DNA 触发了 IFN-β 和抗病毒 IFN 刺激基因表达，从而导致 HSV-1 感染减少。STING 介导的 IFI16 负反馈调节限制了抗病毒免疫过程中 IFN-I 的过度产生，以避免自身免疫性疾病。
