Herpes Simplex ? Virus Antagonizes The Antiviral Innate Immunity Mediated By Ch25h And ?-catenin

Type I interferons(IFNs)are the major components of the antiviral innate immuny.Various pathogen recognition receptors(PRRs)recognize pathogen-associated molecular patterns(PAMPs)generated during the pathogen life cycle and trigger the activation of IFNs signal pathway.IFNs bind to IFN-?/? receptor(IFNAR),resulting in transcription of IFN-stimulated genes(ISGs)to resist a variety of pathogens.Herpes simplex virus type 1(HSV-1)is a double stranded DNA virus which is widespread in the population.It has the ability to attenuate host antiviral machinery and cause a lifelong latent infection.A systematic revealing the underlying mechanism of immune evasion of HSV-1 will provide new cognition about the host-virus interactionPart 1:Herpes simplex virus type 1 abrogates the antiviral activity of C holesterol 25-hydroxylase(Ch25h)via its virion host shutoff protein Ch25h is an interferon-inducible protein,and recent studies have demonstrated that it inhibited the replication of many enveloped viruses.However,in this study,we found that cells infected with wild-type(WT)HSV-1 reduced Ch25h production,and ectopic expression of Ch25h could not inhibit the replication of WT-HSV-1.By screening assay,HSV-1 UL41 protein down-regulated the protein level of Ch25h.In addition,UL41 was shown to abrogate the antiviral activity of Ch25h through degrading its mRNA.Furthermore,ectopic expression of Ch25h inhibited the replication of UL41-null mutant HSV-1(R2621),but not WT-HSV-1,and knockdown of Ch25h did not affect the replication of WT-HSV-I,but promoted the replication of the R2621.For the first time,HSV-1 UL41 was demonstrated to evade the antiviral function of C h25h via its endonuclease activity.Part 2:Herpes Simplex Virus 1 encoded Kinase US3 hyperphosphorylates P-catenin and evades its downstream antiviral innate immune responses.The highly conserved(?-catenin protein in the Wnt signaling pathway is a key factor to enhance the transcription of type I interferon(IFN-I)responsible for innate immune responses.Here(3-catenin was demonstrated to be required for optimal IFN-? production in DNA-sensing signal pathway.We found that the production of IFN-I mediated by?-catenin was antagonized by HSV-1 US3 protein via its kinase activity.US3 interacted with and hyperphosphorylated ?-catenin at Thr 556 to impair ?-catenin-IRF3 interaction and block ?-catenin nuclear translocation The US3 deficiency HSV-1(AUS3 HSV-1)and its kinase mutant viruses(K220M HSV-1 or D305A HSV-1)failed to downregulate the activation of IFN-I signal pathway induced by ?-catenin.For the first time,HSV-1 US3 was shown to abrogate IFN-I production through hyperphosphorylation of?-catenin and subvert host antiviral innate immunity.