Study On The Regulatory Mechanism Of Necroptosis During HSV Infection

Human herpes simplex virus(HSV),a kind of pathogenic virus,is commonly infected around the world.It can not only stay at latentstage across the life span,but also recur sometimes in patients who have accepted the antiviral therapy.It even leads a number of patients' death during severe infection.Programmed cell death is an important host defense strategy to protect cells against virus infection.Apoptosis is a well-defined form of programmed cell death executed by a group of cysteine proteases,called caspases.However,vinuses tend to develop an ability to interfere with apoptosis by encoding multiple anti apoptotic viral proteins.For example,ICP6 that encoded by HSV-1 is capable of binding to caspase-8 and inhibits apoptosis.Recently,necroptosis has been identified as a regulated form of necroptosis that can be invoked in the absence of caspase activity.Once the necroptosis is activated,a multiprotein complex called necrosome would be formed.The major components of the necrosome are receptor-interacting protein(RIP)1 and RIP3.Both RIP1 and RIP3 are protein kinases.The interaction with each other through their homologous RHIM(RIP homotypic interaction motif)domain leads to the phosphorylation and activation of RIP3.Subsequently,the activated RIP3 phosphorylates its substrate MLKL,eventually leading to cell membrane disruption.In our study,HSV encoding R1 protein also contains an RHIM domain.In mouse cells,R1 interacts with RIP3 through the RHIM domain during HSV infection,resulting in necroptosis and the reduced viral replication.In human cells,the associaiton of R1 with RIP lor RIP3 is insufficifent to activate RIP3-dependent necroptosis.R1 competitively disrupts the interaction between RIP1 and RIP3 through the RHIM domain,thereby preventing the formation of necrsome.Hence,R1 inhibits necroptosis to promote viral replication in the natrual human host.Our study not only reveal the physiological functions of necroptosis in the host defense against virus infection,but also provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of necroptosis in human cells...