The Inhibition Mechanism Of Enterovirus 71 Replication By SIRT1

The human enterovirus 71(EV71)is the main pathogen that causes HFMD,severe neurological disorders and even death can occur in severe cases,EV71 possesses a single-stranded positive RNA genome that contains a single open reading frame(ORF)flanked by a 5'untranslated region(5'UTR)and a polyadenylated 3'UTR.EV71 5'UTR RNA is a 745 secondary structure with a clover structure and a ribosomal entry site(IRES),it is closely related with virus RNA translation.Meanwhile,EV71 also includes seven non-structural proteins(2A,2B,2C,3A,3B,3C and 3D)and 4 structural proteins(VP1,VP2,VP3 and VP4).The non-structural protein 3D as an RNA dependent RNA polymerase(RdRp)of EV71 is very important for EV71 RNA replication initiation and RNA extension.Silent information regulation factor 1(SIRT1)as a NAD+ dependent histone deacetylases is widely exists in vivo,its protein size is about 120 kda,belongs to the first type of mammal histone deacetylase,is also most widely studied in histone deacetylases.In the organism,SIRT1 can participate in energy metabolism,tumor development,cell apoptosis and inflammatory response by deacetylation of histone and some non-histone proteins.Although SIRT1 is widely studied,only a few studies have reported the relationship between SIRT1 and the virus,such as SIRT1,which reduces the acetylation level of Tat protein in HIV and thus reduces the rate of HIV replication.There has been no research on the relationship between SIRT1 and EV71.Here,we found that the expression of SIRT1 is up-regulated in EV71 infected cells.More than that the SUMOylation level of SIRT1 was increased which could promote its deacetylase activity.In addition,EV71 also enables SIRT1 to be repositioned from the host cell nucleus to the cytoplasm.Further studies have shown that activated SIRT1 is found to bind EV71 3D protein and inhibit its acetylation level and polymerase activity,this effect attenuates the ability of viral genomes replication.SIRT1 could combine the EV71 5 'UTR RNA in order to suppress the virus RNA transcription,subsequent studies have shown that SIRT1 combined to the 5' UTR of IRES and inhibit RNA translation.To sum up,our research results show that EV71 infection can increase the SIRT1 expression and activity,EV71-activated SIRT1 combined EV71 3D polymerase and 5'UTR clover and IRES of RNA structure,thus inhibiting RNA extension efficiency and the level of translation,eventually inhibit EV71 replication of the genome.The above results reveal the new functions of SIRT1 and explore the new mechanism of potential inhibition of EV71 replication,and provide a research basis for the development of EV71 drugs.