Human OTUD6B positively regulates type I IFN antiviral innate immune responses by deubiquitinating and stabilizing IRF3

Abstract Elaborate regulation of innate immunity is necessary for the host to effectively respond to invading pathogens. As an important component of antiviral immunity transcription factors, the stability and activity of IFN regulatory factor 3 (IRF3) are tightly controlled via multiple post-translational modifications. Here, we identified a human ovarian tumor domain-containing deubiquitinase OTUD6B as a positive regulator of IRF3 that facilitates innate antiviral immune signaling. We demonstrated that OTUD6B directly hydrolyzes the lysine 33 (Lys33)-linked polyubiquitin chain at Lys315 of IRF3 by interacting with IRF3, stabilizing the protein level of IRF3, and promoting type I IFN production. Notably, OTUD6B enhanced cellular antiviral responses in vivo , as evidenced by mice that overexpressed human OTUD6B were more resistant to RNA virus infection and had reduced viral load and morbidity. These findings revealed a previously unknown role for OTUD6B in the regulation of innate antiviral immunity and may provide a potential target for enhancing host antiviral defense.