中山大学JCI | 崔隽等发现MAVS棕榈酰化介导抗病毒免疫新机制

当RNA病毒感染时，信号转接器MAVS会在线粒体外膜上形成功能性的聚集体，作为连接病毒与下游抗病毒天然免疫反应的中心枢纽。目前已有多种调节MAVS激活的机制，但控制MAVS聚集的检查点尚未被发现。

2024年12月2日，来自中山大学生命科学学院崔隽教授团队在Journal of Clinical Investigation杂志最新发表题为“Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses”的研究论文。

该研究发现MAVS在半胱氨酸79（C79）上发生棕榈酰化，主要由ZDHHC12催化产生，对于巨噬细胞的MAVS聚集和抗病毒天然免疫反应是必需的。值得注意的是，系统性红斑狼疮的MAVS发生相关的突变（C79F），导致其棕榈酰化有缺陷，产生低水平的I型干扰素（IFN）。 相应地，Zdhhc12缺乏明显损害RNA病毒诱导的I型IFN反应，Zdhhc12缺乏的小鼠对致命病毒高度易感。

这些发现揭示了一种以前未知的机制，即MAVS的棕榈酰化是病毒感染期间确保其聚集并及时激活的检查点。

Abstract

Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus–associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus–induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.