Viral Transcriptional Regulator Hijacks DHX9 to Evade Innate Immunity
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 would provide fundamental insights for developing anti-viral strategies. Using Mammalian orthoreovirus (REOV) as a model system, we identified a new viral mechanism by which viruses antagonize the host innate immune response. We found that the REOV outer capsid protein s3 functions as a vTR that limits RNA polymerase II (Pol II) recruitment to the promoter regions of NF-?B-dependent genes via its direct interaction with the host helicase DHX9. s3 competes with DHX9 for its interaction with Pol II, resulting in a marked attenuation of Pol II loading onto chromatin. More interestingly, s3 also suppresses DHX9 helicase activity, resulting in the aberrant accumulation of R-loops at promoter-proximal regions and a decrease in NF-?B-dependent gene expression. Together, our findings reveal an unprecedented strategy employed by a viral protein that regulates anti-viral gene expression by directly modulating the host transcription factor DHX9.