Fang Han, Shi Mengling, Wang Cong, Zhang Saiting, Kong Na, Ji Mengyao, Wang Yan, Zhou Yidan, Zhu Qiyun, Zhang Yu, Du Shishen, Xu Shuai, Lei Caoqi
State Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, Hubei 430072, China.
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Proc Natl Acad Sci U S A. 2025 Feb 25;122(8):e2412206122. doi: 10.1073/pnas.2412206122. Epub 2025 Feb 18.
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus-host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.
病毒感染时，视黄酸诱导基因-I（RIG-I）样受体（RLRs）可检测病毒RNA以启动抗病毒天然免疫反应，该反应由线粒体接头蛋白VISA（病毒诱导信号接头蛋白，也称为线粒体抗病毒信号蛋白，MAVS）介导。VISA的稳定性和活性受到多种翻译后修饰的严格调控，其中多聚泛素化起着重要作用。包括萎缩素相互作用蛋白4（AIP4）在内的多种E3泛素连接酶介导VISA的多聚泛素化并导致其降解。然而，VISA的多聚泛素化是如何被调控的仍不清楚。在此，我们发现了前蛋白转化酶枯草杆菌蛋白酶/九型（PCSK9）的双重功能，它是胆固醇稳态的关键酶，也是心血管疾病中一个众所周知的治疗靶点，可在细胞外和细胞内调节宿主对RNA病毒的反应。分泌型PCSK9抑制仙台病毒（SeV）和水疱性口炎病毒（VSV）感染，而细胞内PCSK9通过稳定线粒体上的VISA来增强RLRs介导的干扰素（IFN）诱导。病毒感染诱导PCSK9转位至线粒体，在那里它与AIP4竞争VISA，从而抑制其多聚泛素化和降解。因此，PCSK9的过表达增强了VISA介导的针对RNA病毒感染的天然免疫反应，而其缺陷则产生相反的效果，导致病毒更强劲地复制。PCSK9缺陷型小鼠产生较低水平的I型IFN和促炎细胞因子，使其对VSV和甲型流感病毒感染的敏感性增加。总之，我们的发现揭示了PCSK9在病毒-宿主相互作用中的重要且意想不到的作用，有助于理解控制对病毒感染进行适当和有效免疫反应的复杂机制。
