Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes 英文参考文献.docVIP

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Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes 英文参考文献.doc

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Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes 英文参考文献

DysbindinPromotesthePost-EndocyticSortingofG Protein-CoupledReceptorstoLysosomes AaronMarley,MarkvonZastrow* DepartmentsofPsychiatryandCellularandMolecularPharmacology,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica Abstract Background: Dysbindin,acytoplasmicproteinlongknowntofunctioninthebiogenesisofspecializedlysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadlyexpressed,anddopaminereceptorsaremembersofthelargefamilyofGprotein-coupledreceptors(GPCRs)that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigatedthecellularbasisofthisregulation. Methodology/PrincipalFindings:WeusedRNAinterferencetodepleteendogenousdysbindininHEK293andHeLacells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post- endocyticsortingfunctionexplainedtheminimaleffectofdysbindindepletiononD1receptors,whichrecycleefficiently andtraversethelysosomalpathwaytoonlyasmalldegree.Moreover,dysbindinregulatedthedeltaopioidreceptor,amore distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal traffickingofallsignalingreceptors,however,asitsdepletiondidnotdetectablyaffectdown-regulationoftheEGFreceptor tyrosinekinase.Dysbindinco-immunoprecipitatedwithGASP-1(orGPRASP-1),acytoplasmicproteinshownpreviouslyto modulatelysosomaltraffickingofD2dopamineanddeltaopioidreceptorsbydirectinteraction,andwithHRSthatisacore componentoftheconservedESCRTmachinerymed