Control of antiviral innate immune response by protein geranylgeranylation
UMass Chan AffiliationsDivision of Infectious Diseases and Immunology, Department of Medicine
Document TypeJournal Article
Keywordsinnate immune response
Amino Acids, Peptides, and Proteins
Biochemical Phenomena, Metabolism, and Nutrition
Hemic and Immune Systems
Immunology of Infectious Disease
MetadataShow full item record
AbstractThe 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.
Sci Adv. 2019 May 29;5(5):eaav7999. doi: 10.1126/sciadv.aav7999. eCollection 2019 May. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41072
Full author list omitted for brevity. For the full list of authors, see article.
RightsCopyright © 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).
Except where otherwise noted, this item's license is described as 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).