Control of antiviral innate immune response by protein geranylgeranylation.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: eCollection Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-

Adaptor Proteins, Signal Transducing/*metabolism ; Immunity, Innate/*physiology ; Neuropeptides/*metabolism ; Orthomyxoviridae Infections/*immunology ; Protein Prenylation/*immunology ; rac1 GTP-Binding Protein/*metabolism; Adaptor Proteins, Signal Transducing/genetics ; Alkyl and Aryl Transferases/genetics ; Alkyl and Aryl Transferases/metabolism ; Animals ; Endoplasmic Reticulum/immunology ; Endoplasmic Reticulum/metabolism ; Female ; Humans ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/metabolism ; Male ; Mice, Knockout ; Neuropeptides/genetics ; Orthomyxoviridae Infections/metabolism ; Orthomyxoviridae Infections/mortality ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; rac GTP-Binding Proteins/genetics ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein/genetics ; RAC2 GTP-Binding Protein

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 L 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.

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P30 DK058404 United States DK NIDDK NIH HHS; R01 AI110695 United States AI NIAID NIH HHS; I01 BX002943 United States BX BLRD VA; T32 CA009111 United States CA NCI NIH HHS; R37 AI095755 United States AI NIAID NIH HHS

0 (Adaptor Proteins, Signal Transducing)
0 (IPS-1 protein, mouse)
0 (Neuropeptides)
0 (Rac1 protein, mouse)
0 (Tripartite Motif Proteins)
EC 2.3.2.27 (TRIM31 protein, mouse)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.5.- (Alkyl and Aryl Transferases)
EC 2.5.1.- (geranylgeranyltransferase type-I)
EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
EC 2.7.11.1 (Ripk1 protein, mouse)
EC 3.6.5.2 (rac GTP-Binding Proteins)
EC 3.6.5.2 (rac1 GTP-Binding Protein)

Date Created: 20190601 Date Completed: 20200529 Latest Revision: 20231216

20231216

PMC6541464

10.1126/sciadv.aav7999

31149635