Caenorhabditis elegans Myotubularin MTM-1 Negatively Regulates the Engulfment of Apoptotic Cells 英文参考文献.docVIP

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Caenorhabditis elegans Myotubularin MTM-1 Negatively Regulates the Engulfment of Apoptotic Cells 英文参考文献.doc

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Caenorhabditis elegans Myotubularin MTM-1 Negatively Regulates the Engulfment of Apoptotic Cells 英文参考文献

CaenorhabditiselegansMyotubularinMTM-1Negatively RegulatestheEngulfmentofApoptoticCells WeiZou1,2.,QunLu1,2.,DongfengZhao2,WeidaLi2,JamesMapes3,YutingXie2,XiaochenWang2* 1CollegeofBiologicalSciences,ChinaAgriculturalUniversity,Beijing,China,2NationalInstituteofBiologicalSciences,ZhongguancunLifeSciencesPark,Beijing,China, 3Molecular,Cellular,andDevelopmentalBiology,UniversityofColorado,Boulder,Colorado,UnitedStatesofAmerica Abstract Duringprogrammedcelldeath,apoptoticcellsarerecognizedandrapidlyengulfedbyphagocytes.Althoughanumberof geneshavebeenidentifiedthatpromotecellcorpseengulfment,itisnotwellunderstoodhowphagocytosisofapoptotic cellsisnegativelyregulated.HerewehaveidentifiedCaenorhabditiselegansmyotubularinMTM-1asanegativeregulatorof cellcorpseengulfment.Myotubularins(MTMs)constitutealarge,highlyconservedfamilyoflipidphosphatases.MTMgene mutationsareassociatedwithvarioushumandiseases,butthecellularfunctionsofMTMproteinsarenotclearlydefined. WefoundthatinactivationofMTM-1causedsignificantreductionincellcorpsesinstrongloss-of-functionmutantsofced-1, ced-6,ced-7,andced-2,butnotinanimalsdeficientintheced-5,ced-12,orced-10genes.Incontrast,overexpressionofMTM- 1resultedinaccumulationofcellcorpses.ThiseffectisdependentonthelipidphosphataseactivityofMTM-1.Weshow that loss of mtm-1 functionaccelerates the clearance of cell corpses by promoting their internalization. Importantly, the reduction of cell corpses caused by mtm-1 RNAi not only requires the activities of CED-5, CED-12, and CED-10, but also needsthefunctionsofthephosphatidylinositol3-kinases(PI3Ks)VPS-34andPIKI-1.WefoundthatMTM-1localizestothe plasmamembraneinseveralknownengulfingcelltypesandmaymodulatethelevelofphosphatidylinositol3-phosphate (PtdIns(3)P)invivo.WeproposethatMTM-1negativelyregulatescellcorpseengulfmentthroughtheCED-5/CED-12/CED-10 modulebydephosphorylatingPtdIns(3)Pontheplasmamembrane. Citation: Zou W, Lu Q, Zhao D, Li W, Mapes J, et al. (2009) Caenorhabditis elegans Myotubularin MTM-1 Negat