HHV-6B ribonucleotide reductase sequesters NF-κB subunit p65 to inhibit innate immune responses

Human herpesvirus 6B (HHV-6B) belongs to the genus <i>Roseolovirus</i> of the betaherpesvirus subfamily, causing exanthema subitum and encephalitis. Although viral ribonucleotide reductase (RNR) is conserved in betaherpesviruses, it has lost its enzymatic activity. Human cytomegalovirus (HCMV) belongs to the other betaherpesvirus genus, <i>Cytomegalovirus</i>; its RNR inhibits nuclear factor-kappa B (NF-κB) signaling via interaction with the adaptor molecule RIPK1. However, the significance of enzymatically inactive RNR in roseoviruses is unclear. Here, we show that the RNRs from all three human roseoloviruses inhibit NF-κB activation. HHV-6B RNR sequesters NF-κB subunit p65 in the cytoplasm and inhibits its translocation into the nucleus. Silencing HHV-6B RNR increased the expression of inflammatory molecules in infected cells. This study reveals that inhibiting NF-κB is a conserved role of the RNR in betaherpesviruses but that the precise mechanisms responsible for these effects are different.