Mst1-FoxO Signaling Protects Na？ve T Lymphocytes from Cellular Oxidative Stress in Mice 英文参考文献.docVIP

Mst1-FoxOSignalingProtectsNa?¨veTLymphocytesfrom CellularOxidativeStressinMice JuhyunChoi1.,SangphilOh1.,DongjunLee1,HyunJungOh1,JikYoungPark2,SeanBongLee2 ,Dae-Sik Lim1* 1National Research Laboratory of Molecular Genetics, Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology,Daejeon,SouthKorea,2GeneticsofDevelopmentandDiseaseBranch,NationalInstituteofDiabetesDigestiveKidneyDiseases,NationalInstitutesof Health,Bethesda,Maryland,UnitedStatesofAmerica Abstract Background: The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. In C. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase,Mst1,playsaroleinapoptosisinducedbyvarioustypesofapoptoticstress.Mst1alsoregulatesperipheralna?¨veT celltraffickingandproliferationinmice.However,itsfunctionsinmammalsarenotfullyunderstood. Methodology/PrincipalFindings:Here,wereportthattheMst1-FoxOsignalingpathwayplaysacrucialroleinsurvival,but notapoptosis,ofna?¨veTcells.InMst12/2mice,peripheralTcellsshowedimpairedFoxO1/3activationanddecreasedFoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst12/2 T cells, therebyresultinginelevatedlevelsofintracellularreactiveoxygenspecies(ROS)andinductionofapoptosis.Expressionof constitutivelyactiveFoxO3arestoredMst12/2 Tcellsurvival.CrossingMst1transgenicmice(Mst1Tg)withMst12/2mice reduced ROS levels and restored normal numbers of peripheral na?¨ve T cells in Mst1 Tg;Mst12/2 progeny. Interestingly, peripheralTcellsfromMst12/2micewerehypersensitivetoc-irradiationandparaquat-inducedoxidativestresses,whereas thosefromMst1Tgmicewereresistant. Conclusions/Significance: These data support the hypothesis that tolerance to increased levels of intracellular ROS providedbytheMst1-FoxOssignalingpathwayiscrucialforthemaintenanceofna?¨veTcellhomeostasisintheperiphery. Citation: Choi