Human Cytomegalovirus Tegument Protein UL82 And UL44 Antagonize Host Innate Antiviral Response

For a long time,a large number of people have been infected by human cytomegalovirus(HCMV),but many of them were immunized after HCMV infection at their childhood or adolescence.Nowadays,more and more HCMV infection-related diseases have arised and are threathening the health of a growing number of immunocompromised persons including patients suffered from AIDS,radiation injury or malignant tumor,especially the fetuses and the pregnant women,which makes the society pay much more attention to the researches on HCMV infection,including molecular biology,epidemiology and clinical diagnosis.After viral infection,rapid immune responses would come up in our bodies for host defense.Meanwhile,viruses have evolved a series of molecular strateges to achieve the so-called "immune escape" and guarantee self-proliferation.Therefore,whether viral infection causes diseases was mainly determined by the result of the"battle" between the immune check of host and the immune escape of virus.Our bodies' immunity is mainly consists of the innate immunity and the acquired immunity,and the innate immunity is the first line of host defense againat viral invasion.After pathogenic infection,the germline-coded pattern recognition receptors(PRRs)would recognize pathogens-derived pathogen-associated molecular patterns(PAMPs)and active a series of signaling pathways to induce the final expression of type I interferons(IFNs)and downstream antivial genes.Upon DNA virus infection,viral DNA would be recognized by the cytosolic DNA sensor-Cyclic GMP-AMP synthase(cGAS),leading to the activation of cGAS and the synthesis of cyclic GMP-AMP(cGAMP)from ATP and GTP by cGAS.Then,cGAMP function as second messengers which would bind to and activate the endoplasmic-reticulum(ER)-associated adaptor MITA/STING.The activated MITA/STING translocates from the ER to an ER-Golgi intermediate compartment(EGRIC)/Golgi apparatus,and final to the nucleus-peripheral punctate microsomes.During this process,MITA/STING recruits the kinase TBK1,which in turn phosphorylates the transcription factor IRF3,leading to the dimerization and translocation of IRF3 to the nucleus and the ultimate expression of interferons and downstream antiviral genes.It has been reported that HCMV infection mainly activates cGAS-MITA/STING pathway to induce expression of type I IFNs.However,whether HCMV proteins would target c GAS-MITA/STING axis for immune escape is still unknown.Thus,we screened a large number of the HCMV proteins for their ability to inhibit cGAS-mediated activation of IFN-?,leading to our identification of the HCMV tegument protein UL82 and UL44.The first part research showed that UL82 interacted with MITA and impaired MITA-mediated signaling by two mechanisms.At first,UL82 inhibited the translocation of MITA from the ER to perinuclear microsomes by disrupting the MITA-iRhom2-TRAP(3 translocation complex.Second,UL82 also directly impaired the recruitment of TBK1 and IRF3 to the MITA complex.The levels of downstream antiviral genes induced by UL82-deficient HCMV were higher than those induced by wild-type HCMV.Conversely,wild-type HCMV replicated more efficiently than the UL82-deficient mutant.UL44 is a DNA polymerase processivity factor of HCMV.In this study,we certified that UL44 inhibited interferons and inflammatory cytokines production by counteracting IRF3-and p65-mediated innate immunity responses.Overexpression of UL44 inhibited virus-induced the activation of ISRE,IFN-? and NF-?B report in various types of cells.Consistently,knockdown of UL44 potentiated HCMV triggered production of interferons and inflammatory cytokines.Ectopic expression of UL44 enhanced various virus replication by inhibiting host antiviral responses.Additional studies demonstrated that the 156-290 aa domain and L86/87 amino acid residue of UL44 were critical for inhibiting production of interferons and inflammatory cytokines.These findings revealed an important mechanism for HCMV immune evasion and would contribute to the therapy and vaccine design as well as the drug development for HCMV infection-releated diseases.