Borden Lacy
Last active: 3/24/2020

Control of antiviral innate immune response by protein geranylgeranylation.

Yang S, Harding AT, Sweeney C, Miao D, Swan G, Zhou C, Jiang Z, Fitzgerald KA, Hammer G, Bergo MO, Kroh HK, Lacy DB, Sun C, Glogauer M, Que LG, Heaton NS, Wang D
Sci Adv. 2019 5 (5): eaav7999

PMID: 31149635 · PMCID: PMC6541464 · DOI:10.1126/sciadv.aav7999

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 cFLIP 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.

MeSH Terms (18)

Adaptor Proteins, Signal Transducing Alkyl and Aryl Transferases Animals Endoplasmic Reticulum Female Humans Immunity, Innate Macrophages, Alveolar Male Mice, Knockout Neuropeptides Orthomyxoviridae Infections Protein Prenylation rac1 GTP-Binding Protein rac GTP-Binding Proteins Receptor-Interacting Protein Serine-Threonine Kinases Tripartite Motif Proteins Ubiquitin-Protein Ligases

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