Abstract
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
Highlights
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ
Our analyses further revealed that phosphoglycerate mutase family member 5 (PGAM5) regulates IFNβ expression via TBK1/IRF3 dependent pathways and directly interacts with mitochondrial antiviral-signaling protein (MAVS)
Given the fact that PGAM5 is required for intracellular poly(I:C) induced responses, we examined whether PGAM5 may regulate the cellular immune defense to vesicular stomatitis virus (VSV), a virus known to trigger RIG-1 signaling via intracellular viral RNA
Summary
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. Our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection. Viral RNA activates RIG-I or MDA5 and transduces the signal through the mitochondrial antiviral-signaling protein (MAVS) which forms functional prion-like aggregates to activate downstream molecules such as TBK13–7. Prion-like polymerization of MAVS has been shown to promote the activation of antiviral signaling pathways via activating type I IFN responses. In PGAM5 deficient HeLa cells and PGAM5 deficient murine embryonic fibroblasts (MEFs), we demonstrate decreased expression of IFNβ and IFNβ target genes following stimulation with intracellular poly(I:C), when compared to wild-type (WT) cells. We uncovered that PGAM5 regulates the antiviral response via TBK1/IRF3
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