HDAC6 Regulates Epidermal Growth Factor Receptor (EGFR) Endocytic Trafficking and Degradation in Renal Epithelial Cells 英文参考文献.docVIP

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HDAC6 Regulates Epidermal Growth Factor Receptor (EGFR) Endocytic Trafficking and Degradation in Renal Epithelial Cells 英文参考文献.doc

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HDAC6 Regulates Epidermal Growth Factor Receptor (EGFR) Endocytic Trafficking and Degradation in Renal Epithelial Cells 英文参考文献

HDAC6RegulatesEpidermalGrowthFactorReceptor (EGFR)EndocyticTraffickingandDegradationinRenal EpithelialCells WeiLiu1,3,4,LucyX.Fan1,3,XiaZhou1,3,WilliamE.Sweeney,Jr.1,3,EllisD.Avner1,2,3,XiaogangLi1,2,3 * 1DepartmentofPediatrics,MedicalCollegeofWisconsin,Milwaukee,Wisconsin,UnitedStatesofAmerica,2DepartmentofPhysiology,MedicalCollegeofWisconsin, Milwaukee, Wisconsin, United States of America, 3Children’s Research Institute, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America, 4DepartmentofNephrology,TongjiHospital,HuazhongUniversityofScienceandTechnology,Wuhan,China Abstract We present for the first time that histone deacetylase 6 (HDAC6) regulates EGFR degradation and trafficking along microtubulesinPkd1mutantrenalepithelialcells.HDAC6,themicrotubule-associateda-tubulindeacetylase,demonstrates increased expressionandactivityinPkd1 mutantmouseembryonickidney cells.TargetingHDAC6 withageneralHDAC inhibitor,trichostatin(TSA),oraspecificHDAC6inhibitor,tubacin,increasedtheacetylationofa-tubulinanddownregulated theexpressionofEGFRinPkd1mutantrenalepithelialcells.HDAC6wasco-localizedwithEGFinducedendocyticEGFRand endosomes,respectively.InhibitionoftheactivityofHDAC6acceleratedthetraffickingofEGFRfromearlyendosomesto lateendosomesalongthemicrotubules.WithoutEGFstimulationEGFRwasrandomlydistributedwhileafterstimulation withEGFfor30min,EGFRwasaccumulatedarounda-tubulinlabeledmicrotubulebundles.Thesedatasuggestedthatthe Pkd1 mutation induced upregulation of HDAC6 might act to slow the trafficking of EGFR from early endosomes to late endosomesalongthemicrotubulesfordegradationthroughdeacetylatinga-tubulin.Inaddition,inhibitionofHDACactivity decreased the phosphorylation of ERK1/2, the downstream target of EGFR axis, and normalized EGFR localization from apicaltobasolateralinPkd1knockoutmousekidneys.Thus,targetingHDAC6todownregulateEGFRactivitymayprovide apotentialtherapeuticapproachtotreatpolycystickidneydisease. Citation:LiuW,FanLX,ZhouX,Swee