當RNA病毒感染時，訊號轉接器MAVS會線上粒體外膜上形成功能性的聚集體，作為連線病毒與下游抗病毒天然免疫反應的中心樞紐。目前已有多種調節MAVS啟用的機制，但控制MAVS聚集的檢查點尚未被發現。
2024年12月2日，來自中山大學生命科學學院崔雋教授團隊在Journal of Clinical Investigation雜誌最新發表題為“Palmitoylation acts as a checkpoint for MAVS aggregation to promote antiviral innate immune responses”的研究論文。
該研究發現MAVS在半胱氨酸79（C79）上發生棕櫚醯化，主要由ZDHHC12催化產生，對於巨噬細胞的MAVS聚集和抗病毒天然免疫反應是必需的。值得注意的是，系統性紅斑狼瘡的MAVS發生相關的突變（C79F），導致其棕櫚醯化有缺陷，產生低水平的I型干擾素（IFN）。 相應地，Zdhhc12缺乏明顯損害RNA病毒誘導的I型IFN反應，Zdhhc12缺乏的小鼠對致命病毒高度易感。
這些發現揭示了一種以前未知的機制，即MAVS的棕櫚醯化是病毒感染期間確保其聚集並及時啟用的檢查點。
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.
