STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production
STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production
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STING 介导的 IFI16 降解负面控制 I 型干扰素的产生
DOI：
10.1016/j.celrep.2019.09.069
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发表时间：
2019-10-29
期刊：
影响因子：
8.8
通讯作者：
Ma, Feng
中科院分区：
文献类型：
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作者：
Li, Dapei;Wu, Rongsheng;Ma, Feng
γ-干扰素诱导蛋白-16（IFI 16）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，目前还不清楚如何负调控IFI 16，以避免过量的IFN-I的生产和自身免疫。在这里，我们发现STING直接与IFI 16相互作用，并通过招募E3连接酶TRIM 21通过泛素-蛋白酶体途径促进IFI 16降解。IFI 16的1-pyrin区域负责IFI 16-STING相互作用，并且IFI 16的N-末端区域的前三个赖氨酸是导致STING介导的IFI 16泛素化和降解的关键位点。与野生型IFI 16相比，在用IFI 16-K3/4/6 R（一种抗降解的IFI 16突变体）转染的细胞中观察到更高水平的病毒DNA触发IFN-β和抗病毒IFN刺激的基因表达，从而更少的HSV-1感染。STING介导的IFI 16负反馈调节限制抗病毒免疫过程中IFN-I的过度产生，以避免自身免疫性疾病。
gamma-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 wildtype IFI16, a higher level of viral DNA triggered IFN-beta 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.