FAF1 Regulates Antiviral Immunity by Inhibiting MAVS but Is Antagonized by Phosphorylation upon Viral Infection
FAF1 Regulates Antiviral Immunity by Inhibiting MAVS but Is Antagonized by Phosphorylation upon Viral Infection
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FAF1 通过抑制 MAVS 调节抗病毒免疫，但在病毒感染时被磷酸化拮抗
DOI：
10.1016/j.chom.2018.10.006
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发表时间：
2018-12-12
影响因子：
30.3
通讯作者：
Zhang, Long
中科院分区：
文献类型：
--
作者：
Dai, Tong;Wu, Liming;Zhang, Long
线粒体抗病毒信号蛋白（MAVS）是先天免疫受体视黄酸诱导基因1（RIG-I）的一个衔接子，它将病毒RNA的识别与抗病毒信号联系起来。在与RIG-I相互作用后，MAVS通过E3连接酶TRIM 31经历赖氨酸63连接的多聚泛素化，随后聚集以激活下游信号传导效应物。我们发现，支架蛋白FAF 1形成聚集体，负调控MAVS。FAF 1通过与TRIM 31竞争MAVS结合来拮抗MAVS的多聚泛素化和聚集。FAF 1基因敲除小鼠对RNA病毒感染的抵抗力更强，骨髓细胞中的FAF 1缺陷导致先天信号传导增强，体内病毒载量和发病率降低。在病毒感染后，激酶IKK直接磷酸化FAF 1的Ser 556，并触发FAF 1去聚集。此外，Ser 556磷酸化促进FAF 1溶酶体降解，从而缓解MAVS的FAF 1依赖性抑制。这些发现确立了FAF 1作为MAVS的调节剂，并揭示了调节FAF 1以确保及时激活抗病毒防御的机制。
Mitochondrial antiviral signaling protein (MAVS) is an adaptor of the innate immune receptor retinoic acid-inducible gene 1 (RIG-I) that links recognition of viral RNA to antiviral signaling. Upon interacting with RIG-I, MAVS undergoes lysine 63-linked poly-ubiquitination by the E3 ligase TRIM31 and subsequently aggregates to activate downstream signaling effectors. We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS. FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. FAF1 knockout mice are more resistant to RNA virus infection, and FAF1 deficiency in myeloid cells results in enhanced innate signaling and reduced viral load and morbidity in vivo. Upon virus infection, the kinase IKK epsilon directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS. These findings establish FAF1 as a modulator of MAVS and uncover mechanisms that regulate FAF1 to insure timely activation of antiviral defense.