Abstract
RIG-I-like receptors detect viral RNA in infected cells and promote oligomerization of the outer mitochondrial membrane protein MAVS to induce innate immunity to viral infection through type I interferon production. Mitochondrial reactive oxygen species (mROS) have been shown to enhance anti-viral MAVS signalling, but the mechanisms have remained obscure. Using a biochemical oligomerization-reporter fused to the transmembrane domain of MAVS, we found that mROS inducers promoted lipid-dependent MAVS transmembrane domain oligomerization in the plane of the outer mitochondrial membrane. These events were mirrored by Sendai virus infection, which similarly induced lipid peroxidation and promoted lipid-dependent MAVS transmembrane domain oligomerization. Our observations point to a role for mROS-induced changes in lipid bilayer properties in modulating antiviral innate signalling by favouring the oligomerization of MAVS transmembrane domain in the outer-mitochondrial membrane.
Highlights
Detection of viruses by pathogen associated molecular pattern (PAMP) receptors leads to the secretion of type I interferons (IFN), which bind to IFN receptors and stimulate the expression of genes that inhibit virus replication and spread
Treatment of cells with both rotenone and 0.1μg/ml poly(I:C)-LV led to a five fold increase in IFN-β transcription (compared to cells treated with 0.1μg/ml poly(I:C)-LV alone), reaching IFN-β transcript levels similar to those observed in cells treated with 10 fold higher concentration of poly(I:C)-LV (1μg/ml) alone
MAVS-TM domain is shown here to oligomerize in response to changes in the outer mitochondrial lipid membrane properties caused by treatment with Mitochondrial reactive oxygen species (mROS) inducers or by Sendai virus infection
Summary
Detection of viruses by pathogen associated molecular pattern (PAMP) receptors leads to the secretion of type I interferons (IFN), which bind to IFN receptors and stimulate the expression of genes that inhibit virus replication and spread. Detection of viral nucleic acids by Toll-like receptors and RIG-I-like receptors (RLRs) initiates this antiviral innate immune response [1]. RLRs comprise RIG-I, which binds to viral 5’-triphosphate RNA, MDA5, which detects viral double stranded RNA, and LGP2, which regulates RIG-I and MDA5 signalling. Binding of viral RNA to RIG-I and MDA5 triggers a conformational change in these proteins that exposes their Caspase Activation and Recruitment Domains (CARD). RIG-I and MDA5 subsequently bind to and activate the mitochondrial antiviral signalling protein (MAVS, known as IPS1, VISA, and CARDIF), presumably via the interaction of the RLR CARD domain with MAVS CARD domain [2].
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