Signaling Flux Redistribution at Toll-Like Receptor Pathway Junctions 英文参考文献.docVIP

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Signaling Flux Redistribution at Toll-Like Receptor Pathway Junctions 英文参考文献.doc

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Signaling Flux Redistribution at Toll-Like Receptor Pathway Junctions 英文参考文献

SignalingFluxRedistributionatToll-LikeReceptor PathwayJunctions KumarSelvarajoo1*,YasunariTakada2,JinGohda3,MohamedHelmy1,ShizuoAkira4,MasaruTomita1, MasaTsuchiya1,Jun-ichiroInoue3,KoichiMatsuo2* 1InstituteforAdvancedBiosciences,KeioUniversity,Tsuruoka,Japan,2DepartmentofMicrobiologyandImmunology,SchoolofMedicine,KeioUniversity,Tokyo,Japan, 3DivisionofCellularandMolecularBiology,Institute ofMedicalScience,TheUniversityofTokyo,Tokyo,Japan,4DepartmentofHostDefense,ResearchInstitutefor MicrobialDiseases,OsakaUniversity,Osaka,Japan Abstract Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expressioninthenucleus.Gainorloss-of-functionmutationsofonemoleculehaveshowntoaffectalternativesignaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutationsofMyD88.Wepredict,usingacomputationalmodelbuiltontheperturbation-responseapproachandthelawof mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR , we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increasedIRF3phosphorylationandinductionofCxcl10andIfit2.Furthermore,increasingtheamountofMyD88incultured cellsshoweddecreasedTRAMbindingtoTLR4.InvestigatinganotherTLR4pathwayjunction,fromTRIFtoTRAF6,RIP1and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2. Thus, we demonstratethatSFRisanovelmechanismforenhancedactivationofalternativepathwayswhenmoleculesatpathway junctionsareremoved.OurdatasuggestthatSFRmayenlightenhithertounexplainableintracellularsignalingalterationsin geneticdiseaseswheregainorlo