Browsing by Author "Swan, Gregory"

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    Control of antiviral innate immune response by protein geranylgeranylation
    (Science Advances, 2019-05) Yang, Shigao; Harding, Alfred T; Sweeney, Catherine; Miao, David; Swan, Gregory; Zhou, Connie; Jiang, Zhaozhao; Fitzgerald, Katherine A; Hammer, Gianna; Bergo, Martin O; Kroh, Heather K; Lacy, D Borden; Sun, Chunxiang; Glogauer, Michael; Que, Loretta G; Heaton, Nicholas S; Wang, Donghai
    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.