College of Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan 430072, China.
J Biol Chem. 2012 Aug 17;287(34):28646-55. doi: 10.1074/jbc.M112.362608. Epub 2012 Jun 28.
Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.
病毒感染激活了几种转录因子，包括 NF-κB 和 IRF3，它们共同诱导 I 型干扰素（IFN）和先天抗病毒反应。MITA（也称为 STING）是一种关键的衔接蛋白，它在 RNA 和 DNA 病原体感染时将病毒感应受体与 IRF3 激活联系起来。在这里，我们表明 E3 泛素连接酶三部分基序蛋白 32（TRIM32）泛素化 MITA，并显著增强了 MITA 介导的 IFN-β诱导。TRIM32 的过表达增强了病毒触发的 IFNB1 表达和细胞抗病毒反应。一致地，TRIM32 的敲低具有相反的效果。TRIM32 与 MITA 相互作用，并位于线粒体和内质网。TRIM32 通过其 E3 泛素连接酶活性将 MITA 靶向 K63 连接的泛素化，在 K20/150/224/236 处，这促进了 MITA 与 TBK1 的相互作用。这些发现表明，TRIM32 通过将 MITA 靶向 K63 连接的泛素化和下游激活，成为针对 RNA 和 DNA 病毒的先天免疫的重要调节蛋白。
