Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, China.
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Mol Cell. 2020 Jul 16;79(2):304-319.e7. doi: 10.1016/j.molcel.2020.06.020.
Accurate regulation of innate immunity is necessary for the host to efficiently respond to invading pathogens and avoid excessive harmful immune pathology. Here we identified OTUD3 as an acetylation-dependent deubiquitinase that restricts innate antiviral immune signaling. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes lysine 63 (Lys63)-linked polyubiquitination of MAVS and thus shuts off innate antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its Lys129 residue. In response to virus infection, the acetylated Lys129 is removed by SIRT1, which promptly inactivates OTUD3 and thus allows timely induction of innate antiviral immunity. Importantly, acetyl-OTUD3 levels are inversely correlated with IFN-β expression in influenza patients. These findings establish OTUD3 as a repressor of MAVS and uncover a previously unknown regulatory mechanism by which the catalytic activity of OTUD3 is tightly controlled to ensure timely activation of antiviral defense.
准确调控固有免疫对于宿主有效应对入侵病原体并避免过度有害的免疫病理非常重要。在这里，我们鉴定出 OTUD3 是一种依赖于乙酰化的去泛素化酶，它限制了固有抗病毒免疫信号。OTUD3 在小鼠中的缺失导致固有免疫增强、病毒载量降低和发病率降低。OTUD3 直接水解 MAVS 的赖氨酸 63（Lys63）连接的多泛素化，从而关闭固有抗病毒免疫反应。值得注意的是，OTUD3 的催化活性依赖于其赖氨酸 129 残基的乙酰化。在病毒感染时，SIRT1 去除乙酰化的赖氨酸 129，从而迅速失活 OTUD3，从而允许及时诱导固有抗病毒免疫。重要的是，乙酰化-OTUD3 水平与流感患者 IFN-β 的表达呈负相关。这些发现确立了 OTUD3 作为 MAVS 的抑制剂，并揭示了一个以前未知的调节机制，通过该机制，OTUD3 的催化活性受到严格控制，以确保及时激活抗病毒防御。
