MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3
MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3
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MAVS 通过 E3 连接酶 TRAF3 靶向 ASC 进行 K63 连接泛素化，从而促进炎症小体激活
DOI：
10.4049/jimmunol.1402851
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发表时间：
2015-05-15
影响因子：
4.4
通讯作者：
Zhong, Hui
中科院分区：
文献类型：
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作者：
Guan, Kai;Wei, Congwen;Zhong, Hui
炎性小体信号通路的严格调控对于维持免疫平衡非常重要，但对其严格调控的分子机制仍知之甚少。在这项研究中，我们发现依赖于线粒体抗病毒信号蛋白（MAVS）的信号通路是最佳激活阿尔茨海默病相关斑点样蛋白（ASC）依赖性炎性小体所必需的。特别是，发现TNFR相关因子3是ASC的直接E3连接酶。ASC在Lys174处的泛素化对于斑点形成和炎性小体激活至关重要。MAVS或TNFR相关因子3的缺乏损害ASC泛素化和胞质聚集体形成，导致RNA病毒感染后炎性小体反应降低。这项研究已经确定了以前未被认识到的MAVS在炎症体信号转导的调节中的作用，并提供了对ASC泛素化通过形成ASC斑点控制炎症体活性的机制的分子见解。
Stringent control of inflammasome signaling pathway is important for maintaining immunological balance, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. In this study, we found that the signaling pathway dependent on mitochondrial antiviral signaling protein (MAVS) was required for the optimal activation of apoptosis-associated specklike protein (ASC)–dependent inflammasome. In particular, TNFR-associated factor 3 was found to be a direct E3 ligase for ASC. Ubiquitination of ASC at Lys174 was critical for speck formation and inflammasome activation. Deficiency in MAVS or TNFR-associated factor 3 impaired ASC ubiquitination and cytosolic aggregates formation, resulting in reduced inflammasome response upon RNA virus infection. This study has identified a previously unrecognized role of MAVS in the regulation of inflammasome signaling and provided molecular insight into the mechanisms by which ubiquitination of ASC controls inflammasome activity through the formation of ASC specks.