Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3.

Interferon (IFN)-mediated innate immune defense is a potent antiviral mechanism. Viruses evade innate immunity and limit secretion of beta interferon (IFN-β) to replicate and survive in the host. The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinase (DUB) motif embedded in its N terminus, denoted UL36 ubiquitin-specific protease (UL36USP). In the present study, we demonstrate that HSV-1 UL36USP inhibits Sendai virus (SeV)-induced interferon regulatory factor 3 (IRF3) dimerization, promoter activation, and transcription of IFN-β. The DUB activity of UL36USP is essential to block IFN-β production. UL36USP also inhibited IFN-β promoter activity induced by overexpression of the N terminus of RIG-I (RIG-IN) and MAVS, but not TBK-1, IκB kinase ε (IKKε), and IRF3/5D. UL36USP was subsequently shown to deubiquitinate TRAF3 and prevent the recruitment of the downstream adaptor TBK1. The recombinant HSV-1 lacking UL36USP DUB activity was generated. Cells infected with the mutant virus produced more IFN-β than wild-type (WT) HSV-1-infected cells. These findings demonstrate HSV-1 UL36USP removes polyubiquitin chains on TRAF3 and counteracts the IFN-β pathway.

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