State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
EMBO J. 2020 Jun 2;39(11):e103285. doi: 10.15252/embj.2019103285. Epub 2020 Apr 17.
RLR-mediated type I IFN production plays a pivotal role in innate antiviral immune responses, where the signaling adaptor MAVS is a critical determinant. Here, we show that MAVS is a physiological substrate of SIRT5. Moreover, MAVS is succinylated upon viral challenge, and SIRT5 catalyzes desuccinylation of MAVS. Mass spectrometric analysis indicated that Lysine 7 of MAVS is succinylated. SIRT5-catalyzed desuccinylation of MAVS at Lysine 7 diminishes the formation of MAVS aggregation after viral infection, resulting in the inhibition of MAVS activation and leading to the impairment of type I IFN production and antiviral gene expression. However, the enzyme-deficient mutant of SIRT5 (SIRT5-H158Y) loses its suppressive role on MAVS activation. Furthermore, we show that Sirt5-deficient mice are resistant to viral infection. Our study reveals the critical role of SIRT5 in limiting RLR signaling through desuccinylating MAVS.
RLR 介导的 I 型 IFN 产生在先天抗病毒免疫反应中发挥关键作用，其中信号适配器 MAVS 是一个关键决定因素。在这里，我们表明 MAVS 是 SIRT5 的生理底物。此外，MAVS 在病毒攻击时被琥珀酰化，而 SIRT5 催化 MAVS 的脱琥珀酰化。质谱分析表明 MAVS 的赖氨酸 7 被琥珀酰化。SIRT5 在赖氨酸 7 上催化 MAVS 的脱琥珀酰化，减少了病毒感染后 MAVS 聚集的形成，从而抑制了 MAVS 的激活，并导致 I 型 IFN 产生和抗病毒基因表达受损。然而，SIRT5 的酶缺陷突变体（SIRT5-H158Y）失去了对 MAVS 激活的抑制作用。此外，我们表明 Sirt5 缺陷小鼠对病毒感染具有抗性。我们的研究揭示了 SIRT5 通过脱琥珀酰化 MAVS 来限制 RLR 信号的关键作用。
