A dsRNA Viral Transcriptional Regulator Evades Innate Immunity by Hijacking Host CoTranscription Factor DHX9

Viral transcriptional regulators (vTRs) have emerged as potent factors that shape the host anti-viral gene expression programs. Delineating the molecular mechanisms by which vTRs inhibit or promote transcription will provide fundamental insights for developing anti-viral strategies. Using Mammalian orthoreovirus (REOV) as a model system, a new viral mechanism by which viruses antagonize the host innate immune response is identified. We found that the REOV outer capsid protein σ3 functions as a vTR to suppress NF-κB gene expression via its direct interaction with the host helicase DHX9. Mechanistically, σ3 impairs the initial recruitment of Pol II by disrupting the interaction between DHX9 and Pol II. More interestingly, σ3 suppresses DHX9 helicase activity, resulting in the aberrant accumulation of R-loops at promoter-proximal regions, thereby affecting Pol II pause-release and ultimately suppressing NF-κB gene expression. Together, these findings reveal an unprecedented strategy employed by a viral protein that regulates anti-viral gene expression by directly modulating the host transcription factor DHX9.