The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
复制标题
E3 泛素连接酶 AMFR 和 INSIG1 通过修改适配器 STING 桥接 TBK1 激酶的激活
DOI：
10.1016/j.immuni.2014.11.011
复制
发表时间：
2014-12-18
期刊：
影响因子：
32.4
通讯作者：
Wang, Chen
中科院分区：
文献类型：
--
作者：
Wang, Qiang;Liu, Xing;Wang, Chen
干扰素基因刺激因子（STING，也称为MITA，ERIS或MPYS）是由微生物DNA引发的宿主免疫反应所必需的。然而，STING介导的信号转导的调控机制尚未完全了解。我们在此报道，在细胞质DNA刺激后，内质网（ER）蛋白AMFR以胰岛素诱导基因1（INSIG 1）依赖性方式被募集到STING并与STING相互作用。AMFR和INSIG 1，一种E3泛素连接酶复合物，然后催化STING的K27连接的聚泛素化。这种修饰作为锚定平台，用于招募TANK结合激酶1（TBK 1）并促进其易位到核周微粒体。AMFR或INSIG 1的缺失损害STING介导的抗病毒基因诱导。一致的是，骨髓细胞特异性Insig 1（-/-）小鼠比野生型小鼠更容易感染单纯疱疹病毒1（HSV-1）。这项研究揭示了ER蛋白AMFR和INSIG 1在先天免疫中的重要作用，揭示了STING信号通路中重要的缺失环节。
Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin- induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway.