Abstract
Cytosolic mitochondrial DNA (mtDNA) activates cGAS-mediated antiviral immune responses, but the mechanism by which RNA viruses stimulate mtDNA release remains unknown. Here we show that viroporin activity of influenza virus M2 or encephalomyocarditis virus (EMCV) 2B protein triggers translocation of mtDNA into the cytosol in a MAVS-dependent manner. Although influenza virus-induced cytosolic mtDNA stimulates cGAS- and DDX41-dependent innate immune responses, the nonstructural protein 1 (NS1) of influenza virus associates with mtDNA to evade the STING-dependent antiviral immunity. The STING-dependent antiviral signaling is amplified in neighboring cells through gap junctions. In addition, we find that STING-dependent recognition of influenza virus is essential for limiting virus replication in vivo. Our results show a mechanism by which influenza virus stimulates mtDNA release and highlight the importance of DNA sensing pathway in limiting influenza virus replication.
Highlights
Cytosolic mitochondrial DNA activates cGAS-mediated antiviral immune responses, but the mechanism by which RNA viruses stimulate mtDNA release remains unknown
We demonstrate that viroporin activity of influenza virus M2 or encephalomyocarditis virus (EMCV) 2B protein is essential for cytosolic mtDNA release into the cytosol
We examined the mechanism by which influenza virus stimulates mtDNA release
Summary
Cytosolic mitochondrial DNA (mtDNA) activates cGAS-mediated antiviral immune responses, but the mechanism by which RNA viruses stimulate mtDNA release remains unknown. Recent reports indicate that certain enveloped DNA viruses, including vaccinia virus and murine cytomegalovirus, HSV-1, and retroviruses incorporate and transfer cGAMP to newly infected cells to trigger STINGdependent IFN responses[13,14]. Recent studies highlighted the importance of cytosolic mtDNA in cGAS-mediated antiviral immune responses after infection with certain RNA viruses, such as VSV, lymphocytic choriomeningitis virus (LCMV), Sindbis virus, and dengue virus[17,18,19,20]. NS2B protein degrades cGAS to prevent its activation by cytosolic mtDNA released during dengue virus infection[17] These observations indicate that cytosolic mtDNA promotes cGASSTING-dependent innate antiviral immunity and confers resistance to RNA viruses[17,18,19,20], the mechanism by which RNA virus infection stimulates mtDNA release remains unclear
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