SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation
SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation
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SIRT5 通过催化赖氨酸脱琥珀酰化作用来损害信号适配器 MAVS 的聚集和激活。
DOI：
10.15252/embj.2019103285
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发表时间：
2020-04-17
期刊：
影响因子：
11.4
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
--
作者：
Liu, Xing;Zhu, Chunchun;Xiao, Wuhan
TLR介导的I型IFN产生在先天性抗病毒免疫应答中起关键作用，其中信号转导衔接子MAVS是关键决定因素。在这里，我们表明MAVS是SIRT 5的生理底物。此外，MAVS在病毒攻击后被琥珀酰化，SIRT 5催化MAVS的去琥珀酰化。质谱分析表明MAVS的赖氨酸7被琥珀酰化。SIRT 5催化的MAVS在赖氨酸7处的脱琥珀酰化减少了病毒感染后MAVS聚集的形成，导致MAVS激活受到抑制，并导致I型IFN产生和抗病毒基因表达受损。然而，SIRT 5的酶缺陷突变体（SIRT 5-H158 Y）失去了其对MAVS活化的抑制作用。此外，我们表明Sirt 5缺陷小鼠对病毒感染具有抵抗力。我们的研究揭示了SIRT 5通过去琥珀酰化MAVS在限制RLR信号传导中的关键作用。
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.