Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Alkyl and Aryl Transferases / genetics
-
Alkyl and Aryl Transferases / metabolism
-
Animals
-
Endoplasmic Reticulum / immunology
-
Endoplasmic Reticulum / metabolism
-
Female
-
Humans
-
Immunity, Innate / physiology*
-
Macrophages, Alveolar / immunology
-
Macrophages, Alveolar / metabolism
-
Male
-
Mice, Knockout
-
Neuropeptides / genetics
-
Neuropeptides / metabolism*
-
Orthomyxoviridae Infections / immunology*
-
Orthomyxoviridae Infections / metabolism
-
Orthomyxoviridae Infections / mortality
-
Protein Prenylation / immunology*
-
RAC2 GTP-Binding Protein
-
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
-
rac1 GTP-Binding Protein / metabolism*
Substances
-
Adaptor Proteins, Signal Transducing
-
IPS-1 protein, mouse
-
Neuropeptides
-
Rac1 protein, mouse
-
Tripartite Motif Proteins
-
TRIM31 protein, mouse
-
Ubiquitin-Protein Ligases
-
Alkyl and Aryl Transferases
-
geranylgeranyltransferase type-I
-
Receptor-Interacting Protein Serine-Threonine Kinases
-
Ripk1 protein, mouse
-
rac GTP-Binding Proteins
-
rac1 GTP-Binding Protein