Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans 英文参考文献.docVIP

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Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans 英文参考文献.doc

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Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans 英文参考文献

CalpainsMediateIntegrinAttachmentComplex MaintenanceofAdultMuscleinCaenorhabditiselegans TimothyEtheridge1.,ElizabethA.Oczypok1,2.,SusannLehmann1,BrandonD.Fields2,FreyaShephard1, LewisA.Jacobson2,NathanielJ.Szewczyk1* 1SchoolofGraduateEntryMedicineandHealth,UniversityofNottingham,RoyalDerbyHospital,Derby,UnitedKingdom,2DepartmentofBiologicalSciences,University ofPittsburgh,Pittsburgh,Pennsylvania,UnitedStatesofAmerica Abstract Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recentlyidentifiedasnegativeregulatorsofmuscleproteindegradationandashavingdecreasedmRNAlevelsinresponse to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in musclesizeinresponsetoforceand,perhaps,disuse.Wethereforeinvestigatedtheeffectsofacutedecreasesinexpression ofthegenesencodingthesemulti-proteincomplexes.WefindthatinfullydevelopedadultCaenorhabditiselegansmuscle, RNAiagainstgenesencodingcore,andperipheral,membersofthesecomplexesinducesproteindegradation,myofibrillar andmitochondrialdystrophies,andamovementdefect.GeneticdisruptionofZ-line–orM-line–specificcomplexmembers issufficienttoinducethesedefects.Weconfirmedthatdefectsoccurintemperature-sensitivemutantsfortwoofthegenes: unc-52,whichencodestheextra-cellularligandPerlecan,andunc-112,whichencodestheintracellularcomponentKindlin-2. Theseresultsdemonstratethatintegrincontainingattachmentcomplexes,asawhole,arerequiredforpropermaintenance ofadultmuscle.Thesedefects,andcollapseofarrayedattachmentcomplexesintoballlikestructures,areblockedwhen DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrincontaining complexesresultsincalpain activation.Inwild-typeanimals,eitherduringdevelopment orinadults, RNAiagainstcalpaingenesresultsinintegrinmuscleattachmentdisruptionsandconsequentsub-cellulardefects.These results demonstrate that calpains are requi