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

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 Lys(174) 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.

对炎症小体信号通路的严格控制对于维持免疫平衡非常重要，然而对其严格调控的分子机制仍知之甚少。在这项研究中，我们发现依赖线粒体抗病毒信号蛋白（MAVS）的信号通路是凋亡相关斑点样蛋白（ASC）依赖的炎症小体最佳激活所必需的。特别是，肿瘤坏死因子受体相关因子3被发现是ASC的一种直接E3连接酶。ASC在赖氨酸174位点的泛素化对于斑点形成和炎症小体激活至关重要。MAVS或肿瘤坏死因子受体相关因子3的缺失会损害ASC的泛素化和胞质聚集体的形成，从而导致RNA病毒感染时炎症小体反应降低。这项研究确定了MAVS在炎症小体信号调节中以前未被认识到的作用，并为ASC泛素化通过ASC斑点形成控制炎症小体活性的机制提供了分子层面的见解。