College of Life Sciences, Wuhan University, Wuhan, China.
Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan, China.
Nat Immunol. 2016 Sep;17(9):1057-66. doi: 10.1038/ni.3510. Epub 2016 Jul 18.
STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 ('inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity. iRhom2 recruited the translocon-associated protein TRAPβ to the STING complex to facilitate trafficking of STING from the endoplasmic reticulum to perinuclear microsomes. iRhom2 also recruited the deubiquitination enzyme EIF3S5 to maintain the stability of STING through removal of its K48-linked polyubiquitin chains. These results suggest that iRhom2 is essential for STING activity, as it regulates TRAPβ-mediated translocation and EIF3S5-mediated deubiquitination of STING.
STING 是先天免疫反应 DNA 病毒的核心衔接蛋白。然而，STING 活性的调节方式仍不清楚。我们发现 iRhom2（“无活性的脑回蛋白 2”）是 DNA 病毒触发 I 型干扰素诱导的正调节剂。iRhom2 缺乏显著削弱了细胞中 DNA 病毒和细胞内 DNA 诱导的信号转导，并且 iRhom2 缺陷型小鼠对致死性单纯疱疹病毒 1（HSV-1）感染更敏感。iRhom2 与 STING 持续相关，并通过两种不同的过程来调节 STING 活性。iRhom2 将易位相关蛋白 TRAPβ募集到 STING 复合物中，以促进 STING 从内质网到核周微体的运输。iRhom2 还募集去泛素化酶 EIF3S5 通过去除其 K48 连接的多泛素链来维持 STING 的稳定性。这些结果表明，iRhom2 对于 STING 活性是必不可少的，因为它调节 TRAPβ 介导的易位和 EIF3S5 介导的 STING 去泛素化。
