Herpes Simplex Virus 1 UL36USP Antagonizes Type ?IFN-mediated Antiviral Innate Immunity

Type? interferons(IFNs),as major components of the innate immune system,play a vital role in host resistance to a variety of pathogens.Canonical signaling mediated by Type? IFNs activates the Janus kinase-signal transducer and activator of transcription(JAK-STAT)pathway through binding to IFN-?/? receptor(IFNAR),resulting in transcription of IFN-stimulated genes(ISGs).However,viruses have evolved multiple strategies to evade this response.Herpes simplex virus type 1(HSV-1),a typical member of DNA viruses,is widespread in the population causing lifelong infections.To date,there is no effective vaccine or drug to prevent HSV-1 latent infection,so HSV-1 remains a threat to public health.A leading reason for the success of HSV-1 results from its ability to evade the innate immune response,specifically in inhibiting IFN production.However,so far little is known about the countermeasure by HSV-1 against Type? IFN-mediated signaling.Here,we report that HSV-1 ubiquitin-specific protease(UL36USP)abrogates Type? IFN-mediated signaling independent of its deubiquitinase(DUB)activity.In this study,ectopically expressed UL36 USP inhibited IFN-? induced activation of interferon-stimulated response element(ISRE) and transcription of ISGs.And overexpression of UL36 USP lacking DUB activity also showed similar effect.Furthermore,UL36 USP was demonstrated to antagonize IFN-? induced activation of JAKs and STATs via specifically binding to IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2.More importantly,knockdown of HSV-1 UL36 USP restored the formation of JAK1-IFNAR2 complex.These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting Type? IFN signaling and reveal a novel mechanism of innate immune evasion by HSV-1.