Division of Infectious Diseases and Immunology, Department of Medicine
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Genetic Phenomena | Hemic and Immune Systems | Immunity | Immunology of Infectious Disease | Immunopathology | Virus Diseases | Viruses
The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.
innate immune response, antiviral, signaling protein, protein geranylgeranylation
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Copyright © 2019. The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
DOI of Published Version
Sci Adv. 2019 May 29;5(5):eaav7999. doi: 10.1126/sciadv.aav7999. eCollection 2019 May. Link to article on publisher's site
Yang, Shigao; Jiang, Zhaozhao; Fitzgerald, Katherine A.; and Wang, Donghai, "Control of antiviral innate immune response by protein geranylgeranylation" (2019). Open Access Articles. 3863.
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This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Genetic Phenomena Commons, Hemic and Immune Systems Commons, Immunity Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Virus Diseases Commons, Viruses Commons