GCN2 Has Inhibitory Effect on Human Immunodeficiency Virus-1 Protein Synthesis and Is Cleaved upon Viral Infection 英文参考文献.docVIP

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GCN2 Has Inhibitory Effect on Human Immunodeficiency Virus-1 Protein Synthesis and Is Cleaved upon Viral Infection 英文参考文献.doc

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GCN2 Has Inhibitory Effect on Human Immunodeficiency Virus-1 Protein Synthesis and Is Cleaved upon Viral Infection 英文参考文献

GCN2HasInhibitoryEffectonHumanImmunodeficiency Virus-1ProteinSynthesisandIsCleaveduponViral Infection JavierdelPino1,Jose′ LuisJime′nez2,Iva′nVentoso1,AlfredoCastello′1¤,MaAngeles′ Mun?oz-Ferna′ndez3, Ce′sardeHaro1,JuanJose′ Berlanga1* 1CentrodeBiolog?′aMolecularSeveroOchoa(CSIC-UAM),UniversidadAuto′nomadeMadrid,Madrid,Spain,2PlataformadeLaboratorio,HospitalGeneralUniversitario GregorioMaran?o′n,Madrid,Spain,3LaboratoryofMolecularImmunobiology,HospitalGeneralUniversitarioGregorioMaran?o′n,Madrid,Spain Abstract The reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is a well- characterizedmechanismoftranslationalcontrolinresponsetoawidevarietyofcellularstresses,includingviralinfection. Beside PKR, the eIF2alpha kinase GCN2 participates in the cellular response against viral infection by RNA viruses with centralnervoussystemtropism.PKRhasalsobeeninvolvedintheantiviralresponseagainstHIV-1,althoughthisantiviral effectisverylimitedduetothedistinctmechanismsevolvedbythevirustocounteractPKRaction.Herewereportthat infectionofhumancellswithHIV-1conveystheproteolyticcleavageofGCN2andthatpurifiedHIV-1andHIV-2proteases producedirectproteolysisofGCN2invitro,abrogatingtheactivationofGCN2byHIV-1RNA.Transfectionofdistinctcell lineswithaplasmidencodinganHIV-1cDNAclonecompetentforasingleroundofreplicationresultedintheactivationof GCN2andthesubsequenteIF2alphaphosphorylation.Moreover,transfectionofGCN2knockoutcellsorcellswithlowlevels ofphosphorylatedeIF2alphawiththesameHIV-1cDNAcloneresultedinamarkedincreaseofHIV-1proteinsynthesis.Also, the over-expression of GCN2 in cells led to a diminished viral protein synthesis. These findings suggest that viral RNA produced during HIV-1 infection activates GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleavesGCN2toovercomeitsantiviraleffect. Citation:delPinoJ,Jime′nezJL,VentosoI,Castello′ A,Mun?oz-Ferna′ndezMA′,etal.(2012)GCN2HasInhibitoryEff