Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.