Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity
Acetylation-Dependent Deubiquitinase OTUD3 Controls MAVS Activation in Innate Antiviral Immunity
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乙酰化依赖性去泛素酶 OTUD3 控制先天抗病毒免疫中 MAVS 的激活
DOI：
10.1016/j.molcel.2020.06.020
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发表时间：
2020
期刊：
影响因子：
16
通讯作者：
Zhou F
中科院分区：
文献类型：
--
作者：
Zhang Z;Fang X;Wu X;Ling L;Chu F;Li J;Wang S;Zang J;Zhang B;Ye S;Zhang L;Yang B;Lin S;Huang H;Wang A;Zhou F
准确的天然免疫调节是宿主有效应对入侵病原体、避免过度有害的免疫病理所必需的。在这里，我们确定OTUD3是一种乙酰化依赖的脱泛素酶，它限制了先天抗病毒免疫信号。OTUD3缺乏会导致小鼠的先天免疫增强，病毒载量减少，并导致发病率下降。OTUD3直接水解赖氨酸63(Lys63)连接的MAV的多泛素化，从而关闭先天抗病毒免疫反应。值得注意的是，OTUD3的催化活性依赖于其Lys129残基的乙酰化。作为对病毒感染的反应，乙酰化的Lys129被SIRT1去除，从而迅速灭活OTUD3，从而及时诱导先天抗病毒免疫。重要的是，流感患者的乙酰-OTUD3水平与干扰素-β的表达呈负相关。这些发现确立了OTUD3是MAV的抑制子，并揭示了一种先前未知的调节机制，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。
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.OTUD3deficiency 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.