State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
National Institute of Biological Sciences, Beijing 102206, China.
Nat Commun. 2017 May 4;8:15138. doi: 10.1038/ncomms15138.
Innate immunity plays a pivotal role in virus infection. RIG-I senses viral RNA and initiates an effective innate immune response for type I interferon production. To transduce RIG-I-mediated antiviral signalling, a mitochondrial protein MAVS forms prion-like aggregates to activate downstream kinases and transcription factors. However, the activation mechanism of RIG-I is incompletely understood. Here we identify two ubiquitin enzymes Ube2D3 and Ube2N through chromatographic purification as activators for RIG-I on virus infection. We show that together with ubiquitin ligase Riplet, Ube2D3 promotes covalent conjugation of polyubiquitin chains to RIG-I, while Ube2N preferentially facilitates production of unanchored polyubiquitin chains. In the presence of these polyubiquitin chains, RIG-I induces MAVS aggregation directly on the mitochondria. Our data thus reveal two essential polyubiquitin-mediated mechanisms underlying the activation of RIG-I and MAVS for triggering innate immune signalling in response to viral infection in cells.
先天免疫在病毒感染中起着关键作用。RIG-I 感知病毒 RNA 并启动有效的先天免疫反应以产生 I 型干扰素。为了转导 RIG-I 介导的抗病毒信号，一种线粒体蛋白 MAVS 形成似朊病毒样聚集物以激活下游激酶和转录因子。然而，RIG-I 的激活机制尚不完全清楚。在这里，我们通过色谱纯化鉴定了两种泛素酶 Ube2D3 和 Ube2N，它们是病毒感染中 RIG-I 的激活剂。我们表明，与泛素连接酶 Riplet 一起，Ube2D3 促进 RIG-I 上多泛素链的共价连接，而 Ube2N 则优先促进无连接多泛素链的产生。在这些多泛素链存在的情况下，RIG-I 直接在线粒体上诱导 MAVS 聚集。因此，我们的数据揭示了两种基本的多泛素介导的机制，它们在病毒感染细胞中触发先天免疫信号的 RIG-I 和 MAVS 激活中起作用。
