Host Factor MxB Inhibits The Action And Mechanism Of LINE-1 Retrotransposon

Long interspersed element 1(LINE-1)is the only autonomously active transposable element in the human genome,and account for approximately 17%.Great majority of L1 elements are molecular fossils that are no longer capable of mobilization,LINE-1 still has approximately 80-100 active copies in human genome.Retrotransposition of L1 can result in significant deletions and mutations of genomic sequence,and impacts genomic stability.Genomic stability and human evolution are interdependent and contradictory.Survival of healthy human requires the relative stability of the genome,but the evolution of life depends on mutations.Once overactive of LINE-1,it will cause many of deseases,such as autoimmunity disease,neurological disorders and cancers.Given the mutagenic nature of LINE-1 retrotransposition,cells have developed various defense mechanisms to restrict LINE-1 mobilization.DNA methylation of 5'UTR,RNA interference dependent manner,and active of autophagy pathway are effective manners of control.One arsenal of mechanisms are provided by innate immune factors that have been shown to inhibit virus infections,such as APOBACE3 family,MOV10,SAMHD1,TREX1,RNASLE,ZAP.MxA and MxB are dynamin-like large GTPases.They have been reported to inhibit distinct groups of viruses by different mechanisms.MxA is cytoplasmic,inhibits a plethora of viruses from diverse families,but not HIV-1.In contrast,much fewer viruses have been reported to be restricted by MxB which is is located to the nuclear envelope.MxB,but not MxA,inhibits the replication of HIV-1 in cell culture.It was conceivable that MxB would target the viral capsid after its entry into the cell.Resently,other studies showed that MxB can also inhibit HCV,HBV and HSV replication in cell.In 2015,a research group screen many viral restriction factors of ISGs,detected than MxB can inhibit LINE-1-EGFP reporter(99-PUR-RPS-EGFP)activity,but the active region and the mechanism is unclear.To research the mechanism and active region of MxB inhibit LINE-1 retrotransposition can not only promote the development of endogenouse gene elements regulation,but also provide reference to MxB restrict virus and explain the role of MxB in cell life.Here,we report that a cellular antiviral protein,myxovirus resistance protein B(MxB),restricts the mobilization of LINE-1.This function of MxB requires the nuclear localization signal located at its N-terminus.its GTPase activity and its ability to form oligomers.We further found that MxB associates with LINE-1 protein ORF1p and enhances sequestration of ORF1p to G3BP1-containing cytoplasmic granules.Since knockdown of stress granule marker proteins G3BP1 or TIA 1 abolishes MxB inhibition of LINE-1.we conclude that MxB engages stress granule components to effectively stall LINE-1 proteins within the cytoplasmic granules,thus prevent LINE-1 from entering the nucleus to attempt retrotransposition.Futher more,we next determined whether MxB are required on the inhibition of endogenous retroviruses IAP and MusD.Human MxB can also inhibit IAP and MusD significantly.We also interested in LINE-1 inhibition potency in other species.African green monkey(AGM)and Macaca mulatta(MAC).MxB have strong anti-LINE-1 activity,but the MxA homologue Mxl and Mx2 from mouse can not impact LINE-1 mobilization,the same phenomenon was detected in IAP and MusD replication.Thus.LINE-1 and endogenous retroviruses IAP and MusD inhibition appears to be a conserved feature for primates MxB.Above all.MxB is an antiviral host factor,also has the effect of significantly inhibiting LINE-1 retrotransposon and endogenous retroviruses.By restricting ORF1p import into the nucleus,MxB regulates the abnormal transposition of LINE-1 in cells,thus maintaining the stability of the cell genome.