Small Molecule Control of Virulence Gene Expression in Francisella tularensis 英文参考文献.docVIP

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Small Molecule Control of Virulence Gene Expression in Francisella tularensis 英文参考文献.doc

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Small Molecule Control of Virulence Gene Expression in Francisella tularensis 英文参考文献

SmallMoleculeControlofVirulenceGeneExpressionin Francisellatularensis JamesC.Charity1,LeeAnnT.Blalock2,MichelleM.Costante-Hamm1,DennisL.Kasper2,3,SimonL. Dove1* 1Division of Infectious Diseases, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2Department of Microbiology and MolecularGenetics,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3ChanningLaboratory,DepartmentofMedicine,BrighamandWomen’s Hospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract In Francisella tularensis, the SspA protein family members MglA and SspA form a complex that associates with RNA polymerase (RNAP) to positively control the expression of virulence genes critical for the intramacrophage growth and survivaloftheorganism.AlthoughtheassociationoftheMglA-SspAcomplexwithRNAPisevidentlycentraltoitsrolein controllinggeneexpression,themoleculardetailsofhowMglAandSspAexerttheireffectsarenotknown.Hereweshow thatinthelivevaccinestrainofF.tularensis(LVS),theMglA-SspAcomplexworksinconcertwithaputativeDNA-binding proteinwehavecalledPigR,togetherwiththealarmoneguanosinetetraphosphate(ppGpp),toregulatetheexpressionof targetgenes.Inparticular,wepresentevidencethatMglA,SspA,PigRandppGppregulateexpressionofthesamesetof genes,andshowthatmglA,sspA,pigRandppGppnullmutantsexhibitsimilarintramacrophagegrowthdefectsandare strongly attenuated for virulence in mice. We show further that PigR interacts directly with the MglA-SspA complex, suggestingthatthecentralroleoftheMglAandSspAproteinsinthecontrolofvirulencegeneexpressionistoserveasa targetforatranscriptionactivator.Finally,wepresentevidencethatppGppexertsitseffectsbypromotingtheinteraction betweenPigRandtheRNAP-associatedMglA-SspAcomplex.ThroughitsresponsivenesstoppGpp,thecontactbetween PigRandtheMglA-SspAcomplexallowstheintegrationofnutritionalcuesintotheregulatorynetworkgoverningvirulence geneexpression. Citation: Charity JC, Blalock LT, Costante-Hamm MM, Kasper DL,