MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity

• 成果类型: Article
• 署名作者: Liu, Yinong; Hou, Dan; Chen, Wenzhe; Lu, Xuan; Komaniecki, Garrison P.; Xu, Yilai; Yu, Tao; Zhang, Sophia M.; Linder, Maurine E.; Lin, Hening
• 署名单位: University of Wisconsin System; University of Wisconsin Parkside; Cornell University; Cornell University; Howard Hughes Medical Institute; Cornell University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14405
• DOI: 10.1073/pnas.2403392121
• 发表日期: 2024-08-20
• 关键词: rig-i; signaling protein; s-palmitoylation; adapter protein; rna helicase; interferon; localization; inhibitors

摘要

Cysteine palmitoylation or S- palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S- palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA- sensing RIG- I- like receptors. Here, we identify that MAVS, a C- terminal tail- anchored mitochondrial outer membrane protein, is S- palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail- anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail- anchor, without regulation by Cys508 S- palmitoylation. However, upon viral infection, MAVS S- palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S- palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S- palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS- related autoimmune diseases.