Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia.
Immunol Cell Biol. 2013 Apr;91(4):321-30. doi: 10.1038/icb.2013.7. Epub 2013 Feb 12.
The innate immune response to virus must be balanced to eliminate infection yet limit damaging inflammation. A critical arm of the antiviral response is launched by the retinoic acid-inducible-gene I (RIG-I) protein. RIG-I is activated by viral RNA then associates with the mitochondrial antiviral signaling (MAVS) protein to subsequently induce potent inflammatory cytokines. Here, we demonstrate the mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is a crucial moderator of RIG-I signaling. MUL1 is localized to the mitochondria where it interacts with MAVS and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiated RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosted the antiviral response and increased proinflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. We therefore submit that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.
先天免疫反应必须平衡以消除感染，但又要限制炎症损伤。抗病毒反应的一个关键部分是由视黄酸诱导基因 I（RIG-I）蛋白启动的。RIG-I 被病毒 RNA 激活，然后与线粒体抗病毒信号（MAVS）蛋白结合，随后诱导强烈的炎症细胞因子。在这里，我们证明线粒体 E3 泛素蛋白连接酶 1（MUL1）是 RIG-I 信号的关键调节剂。MUL1 定位于线粒体，在那里它与 MAVS 相互作用，并催化 RIG-I 的翻译后修饰，抑制 RIG-I 依赖性细胞信号转导。因此，MUL1 的耗竭增强了 RIG-I 介导的核因子-κB（NF-κB）和干扰素（IFN）β报告基因活性。此外，在用 RNA 模拟物聚 I:C 和仙台病毒进行攻击后，MUL1 的耗竭增强了抗病毒反应并增加了促炎细胞因子。因此，我们提出 MUL1 是 RIG-I 样受体依赖性抗病毒反应的新型调节剂，其作用是限制炎症。
