The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response.
The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response.
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E3 泛素连接酶 RNF185 促进 cGAS 介导的先天免疫反应
DOI：
10.1371/journal.ppat.1006264
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发表时间：
2017-03
期刊：
影响因子：
6.7
通讯作者：
Zhou Q
中科院分区：
文献类型：
--
作者：
Wang Q;Huang L;Hong Z;Lv Z;Mao Z;Tang Y;Kong X;Li S;Cui Y;Liu H;Zhang L;Zhang X;Jiang L;Wang C;Zhou Q
环鸟苷酸 - 腺苷酸合酶（cGAS）在胞质DNA刺激下，催化形成第二信使2′3′ - 环鸟苷酸 - 腺苷酸（2′3′ - cGAMP），后者随后与干扰素基因刺激因子（STING）结合并激活下游信号传导。cGAS酶活性如何被动态调节仍有待阐明。在此，我们报道内质网泛素连接酶RNF185在单纯疱疹病毒1型（HSV - 1）感染期间与cGAS相互作用。RNF185的异位表达或敲低分别增强或削弱了干扰素调节因子3（IRF3）应答基因的表达。从机制上讲，RNF185特异性地催化cGAS的K27连接的多聚泛素化，从而促进其酶活性。此外，系统性红斑狼疮（SLE）患者的RNF185 mRNA表达升高。总之，这项研究揭示RNF185是cGAS的首个E3泛素连接酶，为先天免疫应答中cGAS活性的调节提供了线索。
泛素化已被证明是一种有效的手段，可催化宿主面对微生物时激活的快速、动态和多样的调节过程。鉴于胞质DNA感应通路在抗病毒先天免疫应答和自身免疫疾病发病机制中的关键作用，它们受到多种时空调节，从而塑造信号通路的强度和持续时间。近期的研究进展已将环鸟苷酸 - 腺苷酸合酶（cGAS）确定为启动干扰素基因刺激因子（STING）依赖性信号通路的主要DNA传感器。然而，cGAS活性如何被动态调节仍知之甚少。在本研究中，我们确定E3泛素连接酶RNF185是cGAS - STING信号传导的正向调节剂。RNF185的敲低显著减弱IRF3应答基因的表达。内质网驻留的RNF185与cGAS相互作用，并在HSV - 1感染时催化cGAS的K27连接的多聚泛素化，从而增强cGAS的酶活性。值得注意的是，系统性红斑狼疮（SLE）患者的RNF185 mRNA表达升高。我们的研究揭示RNF185是cGAS的首个E3泛素连接酶，并表明RNF185是调节抗病毒反应的重要靶点。
The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2′3′-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression. Mechanistically, RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity. Additionally, Systemic Lupus Erythematosus (SLE) patients displayed elevated expression of RNF185 mRNA. Collectively, this study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS, shedding light on the regulation of cGAS activity in innate immune responses. Ubiquitination has been demonstrated to serve as an effective means to catalyze the rapid, dynamic and versatile regulatory processes that are activated when hosts face microbes. Given the critical functions of cytosolic DNA sensing pathway in anti-viral innate immune responses and the pathogenesis of autoimmune diseases, they are subjected to manifold spatial and temporal modulations shaping the strength and duration of the signaling pathways. Recent progress has characterized the cyclic GMP-AMP synthase (cGAS) as the primary DNA sensor that initiates stimulator of interferon genes (STING)-dependent signaling pathway. However, it remains poorly understood how cGAS activity is modulated dynamically. In this study, we identify E3 ubiquitin ligase RNF185 as a positive regulator of cGAS-STING signaling. Knockdown of RNF185 significantly attenuates IRF3-responsive gene expression. ER-resident RNF185 interacts with cGAS and catalyzes the K27-linked poly-ubiquitination of cGAS upon HSV-1 challenges, which thus potentiates cGAS enzymatic activity. Notably, systemic lupus erythematosus (SLE) patients have elevated expression of RNF185 mRNA. Our study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS and suggests RNF185 as an important target for modulating antiviral response.