USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA
USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA
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USP49 通过解离 K63 相关的 MITA 泛素化来负调节细胞抗病毒反应
DOI：
10.1371/journal.ppat.1007680
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发表时间：
2019-04-01
期刊：
影响因子：
6.7
通讯作者：
Zhong, Bo
中科院分区：
文献类型：
--
作者：
Ye, Liya;Zhang, Qiang;Zhong, Bo
IRF 3激活介体（Mediator of IRF 3 activation，MITA，也称为STING和ERIS）是细胞质DNA触发信号传导的必需衔接蛋白，并参与先天免疫应答、自身免疫和肿瘤发生。MITA的活性受泛素化和去泛素化的关键调节。在这里，我们报告说，USP 49与HSV-1感染后的MITA相互作用并使其去泛素化，从而降低细胞的抗病毒反应。USP 49的敲除或敲除增强HSV-1、细胞质DNA或cGAMP诱导的I型干扰素（IFN）和促炎细胞因子的产生，并损害HSV-1复制。一致地，与Usp 49（+/+）小鼠相比，Usp 49（-/-）小鼠表现出对致死性HSV-1感染的抗性和减弱的HSV-1复制。在机制上，USP 49在HSV-1感染后从MITA中去除K63连接的泛素链，这抑制了MITA的聚集和随后TBK 1向信号复合物的募集。这些发现表明USP 49在终止先天性抗病毒反应中的关键作用，并提供了对MITA激活的复杂调控机制的见解。作者摘要介导IRF 3激活（MITA）是介导对DNA病毒的先天性免疫反应的重要衔接蛋白。MITA的激活需要K63连接的泛素化和寡聚化，其促进下游激酶的募集和转录因子的磷酸化以诱导下游基因的表达。在我们的研究中，我们发现去泛素化酶USP 49与MITA相互作用并从MITA中去除K63连接的多聚泛素链，以下调抗病毒信号。USP 49缺陷导致细胞和体内HSV-1感染后抗病毒细胞因子的产生增强和病毒复制减弱。因此，我们的研究揭示了MITA活性和细胞抗病毒反应的负反馈调节。
Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49(-/-) mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49(+/+) mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation.Author summary Mediator of IRF3 activation (MITA) is an essential adaptor protein in mediating innate immune responses to DNA viruses. The activation of MITA requires K63-linked ubiquitination and oligomerization which promotes the recruitment of downstream kinases and phosphorylation of transcription factors to induce expression of downstream genes. In our study, we have discovered that the deubiquitinating enzyme USP49 interacts with and removes K63-linked polyubiquitin chains from MITA to downregulate antiviral signaling. USP49 deficiency results in enhanced production of antiviral cytokines and attenuated virus replication after HSV-1 infection in cells and in vivo. Our study thus reveals a negative feedback regulation of MITA activity and cellular antiviral responses.