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Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses.

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.

SUBMITTER: Moriyama M

PROVIDER: S-EPMC6789137 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses.

Moriyama Miyu M Koshiba Takumi T Ichinohe Takeshi T

Nature communications 20191011 1

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 ...[more]

PMID: 31604929

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Project description:Circular RNAs (circRNAs) are an important subclass of noncoding RNAs implicated in the regulation of multiple biological processes. However, the functional involvement of circRNAs in the pathogenesis of influenza A viruses (IAVs) remains largely unknown. Here, we employed RNA sequencing (RNA-Seq) to examine the differentially expressed circRNAs in mouse lung tissues challenged or not challenged with IAV to evaluate the impact of viral infection on circRNAs in vivo. We observed that 413 circRNAs exhibited significantly altered levels following IAV infection. Among these, circMerTK, the derivative of myeloid-epithelial-reproductive tyrosine kinase (MerTK) pre-mRNA, was highly induced by IAV. Interestingly, circMerTK expression was also increased upon infection with multiple DNA and RNA viruses in human and animal cell lines, and thus it was selected for further studies. Poly(I:C) and interferon β (IFN-β) stimulated circMerTK expression, while RIG-I knockout and IFNAR1 knockout cell lines failed to elevate circMerTK levels after IAV infection, demonstrating that circMerTK is regulated by IFN signaling. Furthermore, circMerTK overexpression or silencing accelerated or impeded IAV and Sendai virus replication, respectively. Silencing circMerTK enhanced the production of type I IFNs and interferon-stimulating genes (ISGs), whereas circMerTK overexpression suppressed their expression at both the mRNA and protein levels. Notably, altering circMerTK expression had no effect on the MerTK mRNA level in cells infected or not infected with IAV, and vice versa. In addition, human circMerTK and mouse homologs functioned similarly in antiviral responses. Together, these results identify circMerTK as an enhancer of IAV replication through suppression of antiviral immunity. IMPORTANCE CircRNAs are an important class of noncoding RNAs characterized by a covalently closed circular structure. CircRNAs have been proven to impact numerous cellular processes, where they conduct specialized biological activities. In addition, circRNAs are believed to play a crucial role in regulating immune responses. Nevertheless, the functions of circRNAs in the innate immunity against IAV infection remain obscure. In this study, we employed transcriptomic analysis to investigate the alterations in circRNAs expression following IAV infection in vivo. It was found that expression of 413 circRNAs was significantly altered, of which 171 were upregulated, and 242 were downregulated following the IAV infection. Interestingly, circMerTK was identified as a positive regulator of IAV replication in both human and mouse hosts. CircMerTK was shown to influence IFN-β production and its downstream signaling, enhancing IAV replication. This finding provides new insights into the critical roles of circRNAs in regulating antiviral immunity.

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Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses.

Publications

Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses.

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