MOV10 (Moloney leukemia virus 10, homolog) is an interferon-inducible RNA helicase, associated with small RNA-induced silencing. Here, we report that MOV10 exhibits antiviral activity, independent of its helicase function, against a number of positive and negative-strand RNA viruses by enhancing type I interferon (IFN) induction. Using a number of CRISPR/Cas9-mediated knockout human cells, we show that IRF3-mediated IFN induction and downstream IFN signaling through IFN receptor was necessary to inhibit virus replication by MOV10. MOV10 enhanced IRF3-mediated transcription of IFN. However, this IFN induction by MOV10 was unique and independent of the known RIG-I/MAVS-mediated RNA-sensing pathway. Upon virus infection, MOV10 specifically required IKKε not TBK1, for its antiviral activity. The important role of MOV10 in mediating antiviral signaling was further supported by the finding that viral proteases from picornavirus family specifically targeted MOV10 as a possible innate immune evasion mechanism. These results establish MOV10, an evolutionary conserved protein involved in RNA silencing, as an antiviral gene against RNA viruses that uses a RLR-independent pathway to enhance IFN response.
Members of the interferon-inducible PYHIN protein family such as Absent in Melanoma-2 and Interferon Gamma Inducible Protein (IFI) 16 bind double-stranded DNA (dsDNA) and form caspase-1 activating inflammasomes, important in immunity to cytosolic bacteria, DNA viruses or Human Immunodeficiency Virus. IFI16 has also been shown to regulate transcription of type I Interferons during Herpes Simplex Virus infection. The role of other members of the PYHIN protein family in the regulation of immune responses is much less clear. Here, we identified an immune regulatory function for a member of the murine PYHIN protein family, p205 (also called Ifi205). Examination of immune responses induced by dsDNA and other microbial ligands in bone marrow derived macrophages lacking p205 revealed that inflammasome activation by dsDNA as well as ligands that engage the NLRP3 inflammasome was severely compromised in these cells. Further analysis revealed that p205 knockdown cells showed reduced expression of Asc at the protein and RNA level. p205 knockdown resulted in reduced binding of actively transcribing RNA Polymerase II to the endogenous Asc gene resulting in decreased transcription and processing of Asc pre-mRNA. Deletion of p205 in B16 melanoma cells using CRISPR/Cas9 showed similar loss of Asc expression. Ectopic expression of p205 induced expression of an Asc promoter-luciferase reporter gene. Together these findings suggest that p205 controls expression of Asc mRNA to regulate inflammasome responses. These findings expand on our understanding of immune regulatory roles for the PYHIN protein family.
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