Herpes Simplex Virus Type 1 UL36 Inhibits NF-?B Activation In DNA Sensing Signal Pathway

The innate immune signal pathway to against pathogens begins when pathogen recognition receptors recognize pathogen-associated molecular patterns.The DNA sensing pathway and the NF-?B signaling plays a critical role in establishing the innate immunity.The herpes simplex virus type 1(HSV-1)is a double stranded DNA virus that spreads in the population.HSV-1 encoded tegument protein UL36,which has a deubiquitinase(DUB)domain in its N terminus,is noted as UL36 ubiquitin-specific protease(UL36U SP).However,the host innate antiviral immunity affected by UL36USP is unclear.This project aims to investigate the molecular mechanisms by which UL36USP to counteract the innate antiviral immunity especially DNA sensing signal pathways.Cyclic GMP-AMP synthase(cGAS)is one of the cytoplasmic DNA sensors,it recognizes foreign DNA then mediates signal transduction with stimulator of interferon genes(STING)to inhibit the replication of HSV-1.In this study,ectopically expressed UL36USP blocked interferon(IFN)stimulatory DNA induced IFN-?transcription.UL36USP also inhibited promoter activation of IFN-P and NF-?B induced by cGAS and STING activation.Subsequently,UL36USP was shown to restrict NF-?B activation mediated by overexpression of STING,TANK-binding kinase 1,I?B kinase a(IKKa)and IKK?,but not p65,which suggested that UL36USP inhibited NF-?B signaling at the level between IKK and p65.Furthermore,UL36USP was demonstrated to deubiquitinate I?B? and restrict its degradation but the recombinant HSV-1 lacking UL36USP DUB activity failed to do so.For the first time,UL36USP was shown to dampen NF-?B activation in DNA sensing signaling to evade host antiviral innate immunity,depending on its DUB activity.