SRA Suppresses Antiviral Innate Immune Response in Macrophages by Limiting TBK1 K63 Ubiquitination via Deubiquitinase USP15.
SRA Suppresses Antiviral Innate Immune Response in Macrophages by Limiting TBK1 K63 Ubiquitination via Deubiquitinase USP15.
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SRA 通过去泛素酶 USP15 限制 TBK1 K63 泛素化，抑制巨噬细胞中的抗病毒先天免疫反应
DOI：
10.1128/spectrum.02028-22
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发表时间：
2022-12-21
影响因子：
3.7
通讯作者：
Chen, Qingyun
中科院分区：
文献类型：
--
作者：
Li, Lei;Luo, Jialiang;Zhu, Zhengyumeng;Xu, Qishan;Wang, Ping;Chang, Bo;Wang, Di;Yu, Lu;Lu, Xiao;Zhou, Jia;Zuo, Daming;Chen, Qingyun
在病毒感染期间，PRRs被用来检测特定的病毒成分，如病毒RNA或DNA，并调节受感染细胞或其他免疫细胞的先天免疫反应。我们报道，SRA是一种重要的先天PRR，在体内和体外，SRA的缺乏促进了IRF3的激活，I型干扰素的产生，以及对RNA和DNA病毒的先天抗病毒反应。摘要天然免疫系统是宿主抵御微生物感染的第一道防线。在病毒感染过程中，模式识别受体(PRRs)被用来检测特定的病毒成分，如病毒RNA或DNA，并调节感染细胞或免疫细胞的先天免疫反应。我们先前的研究表明，清道夫受体A(Screvenger Receptor A，SRA)是一种重要的天然PRR，可损害肝细胞中的抗乙肝病毒(HBV)应答。鉴于SRA主要在巨噬细胞中表达，在这里，我们评估了在巨噬细胞中表达的SRA在RNA或DNA病毒感染时的功能。−/−小鼠对水疱性口炎病毒或单纯疱疹病毒1型感染的易感性降低。在感染病毒的srA−/−小鼠中，与野生型(WT)小鼠相比，我们观察到低病毒量伴随着干扰素的增加。此外，SRA显著抑制坦克结合蛋白1和干扰素调节因子3的磷酸化。我们提供的生化证据表明，SRA直接与TBK1的N末端激酶结构域(KD)相互作用，导致其K63连接的泛素化受到限制。此外，我们还证明，SRA通过促进泛素特异性蛋白酶15(USP15)的募集来去泛素化TBK1，从而负向调节TBK1的活性。综上所述，我们在巨噬细胞中确定了SRA与TBK1/IRF3信号通路之间的联系，表明SRA在宿主抗病毒免疫调节中起着关键作用。在病毒感染期间，PRRs具有重要作用，可用于检测特定的病毒成分，如病毒RNA或DNA，并调节受感染细胞或其他免疫细胞中的先天免疫反应。我们报道，SRA是一种重要的先天PRR，在体内和体外，SRA的缺乏促进了IRF3的激活，I型干扰素的产生，以及对RNA和DNA病毒的先天抗病毒反应。此外，生化分析表明，SRA直接与TBK1的Kd结构域相互作用，限制其K63连接的多泛素化，从而降低TBK1的激活。进一步的分析确定，SRA是通过USP15的招募而激活TBK1的调节器，这描述了SRA在先天抗病毒免疫中的一个先前未知的功能。
During virus infection, PRRs are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or other immune cells. We reported that deficiency of SRA, an important innate PRR, promoted IRF3 activation, type I IFN production, and innate antiviral responses against RNA and DNA viruses in vivo and in vitro. ABSTRACT The innate immune system is the first line of host defense against microbial infections. During virus infection, pattern recognition receptors (PRRs) are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or immune cells. Our previous study demonstrated that scavenger receptor A (SRA), an important innate PRR, impaired the anti-hepatitis B virus (HBV) response in hepatocytes. Given that SRA is primarily expressed in macrophages, here, we assessed the function of SRA expressed in macrophages in response to RNA or DNA viral infection. SRA-deficient (SRA−/−) mice showed reduced susceptibility to viral infection caused by vesicular stomatitis virus (VSV) or herpes simplex virus 1 (HSV-1). In the virus-infected SRA−/− mice, compared with their wild-type (WT) counterparts, we observed low amounts of virus accompanied by enhanced interferon (IFN) production. Furthermore, SRA significantly inhibited the phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). We provided biochemical evidence showing that SRA directly interacts with the N-terminal kinase domain (KD) of TBK1, resulting in the limitation of its K63-linked ubiquitination. Moreover, we demonstrated that SRA negatively regulates the activity of TBK1 by promoting the recruitment of ubiquitin-specific protease 15 (USP15) to deubiquitinate TBK1. In summary, we have identified the connection between SRA and the TBK1/IRF3 signaling pathway in macrophages, indicating a critical role of SRA in the regulation of host antiviral immunity. IMPORTANCE During virus infection, PRRs are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or other immune cells. We reported that deficiency of SRA, an important innate PRR, promoted IRF3 activation, type I IFN production, and innate antiviral responses against RNA and DNA viruses in vivo and in vitro. Furthermore, the biochemical analysis showed that SRA directly interacts with the KD domain of TBK1 and limits its K63-linked polyubiquitination, reducing TBK1 activation. Further analyses determined that SRA is a modulator for TBK1 activation via the recruitment of USP15, which delineated a previously unrecognized function for SRA in innate antiviral immunity.
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