Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Immunity. 2010 Nov 24;33(5):765-76. doi: 10.1016/j.immuni.2010.10.013. Epub 2010 Nov 11.
The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses.
先天免疫系统检测到暴露在细胞质中的病原体和宿主来源的双链 DNA，并诱导 I 型干扰素 (IFN) 和其他细胞因子。在这里，我们鉴定出干扰素诱导的三联基序 (TRIM) 56 是双链 DNA 介导的 I 型干扰素诱导的调节剂。TRIM56 过表达增强双链 DNA 刺激后 IFN-β 启动子的激活，而 TRIM56 敲低则消除了这种作用。TRIM56 与 STING 相互作用，并将其靶向赖氨酸 63 连接的泛素化。这种修饰诱导 STING 二聚化，这是抗病毒激酶 TBK1 募集和随后 IFN-β 诱导的前提。总之，这些结果表明 TRIM56 是一种干扰素诱导的 E3 泛素连接酶，可调节 STING 以赋予双链 DNA 介导的先天免疫反应。
