iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING
iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING
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iRhom2 通过介导适配器 STING 的运输和稳定性，对于 DNA 病毒的先天免疫至关重要
DOI：
10.1038/ni.3510
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发表时间：
2016-09-01
影响因子：
30.5
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Luo, Wei-Wei;Li, Shu;Shu, Hong-Bing
STING是对DNA病毒的先天免疫应答中的中心适配器。然而，STING活动的调节方式仍不清楚。我们鉴定了iRhom 2（“无活性菱形蛋白2”）作为DNA病毒触发的I型干扰素诱导的正调节因子。iRhom 2缺陷明显损害了细胞中DNA-病毒-和细胞内-DNA-诱导的信号传导，并且iRhom 2缺陷小鼠对致死性单纯疱疹病毒1型（HSV-1）感染更敏感。iRhom 2与STING组成型相关，并在两个不同的过程中起作用以调节STING活性。iRhom 2将转座子相关蛋白TRAPβ招募到STING复合物中，以促进STING从内质网运输到核周微粒体。iRhom 2还募集去泛素化酶EIF 3S 5以通过去除其K48连接的多聚泛素链来维持STING的稳定性。这些结果表明iRhom 2对于STING活性是必需的，因为它调节TRAPβ介导的易位和EIF 3S 5介导的STING去泛素化。
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.