Control of antiviral innate immune response by protein geranylgeranylation.
Sci Adv
; 5(5): eaav7999, 2019 05.
Article
in En
| MEDLINE
| ID: mdl-31149635
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neuropeptides
/
Protein Prenylation
/
Orthomyxoviridae Infections
/
Rac1 GTP-Binding Protein
/
Adaptor Proteins, Signal Transducing
/
Immunity, Innate
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Sci Adv
Year:
2019
Document type:
Article
Affiliation country:
United States