A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network 英文参考文献.docVIP

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A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network 英文参考文献.doc

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A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network 英文参考文献

AGeneticScreeningStrategyIdentifiesNovelRegulators oftheProteostasisNetwork M.CatarinaSilva1,2,SusanFox1,MonicaBeam1,3,HappyThakkar1,MargaridaD.Amaral2,4,RichardI. Morimoto1* 1DepartmentofMolecularBiosciences,RiceInstituteforBiomedicalResearch,NorthwesternUniversity,Evanston,Illinois,UnitedStatesofAmerica,2FacultyofSciences, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisboa, Lisboa, Portugal, 3Department of Biomedical Engineering, Northwestern University,Evanston,Illinois,UnitedStatesofAmerica,4CentreofHumanGenetics,NationalInstituteofHealth,Lisboa,Portugal Abstract Ahallmarkofdiseasesofproteinconformationandagingistheappearanceofproteinaggregatesassociatedwithcellular toxicity.Wepositthatthefunctionalpropertiesoftheproteostasisnetwork(PN)protecttheproteomefrommisfoldingand combat the proteotoxic events leading to cellular pathology. In this study, we have identified new components of the proteostasis network that can suppress aggregation and proteotoxicity, by performing RNA interference (RNAi) genetic screensformultipleunrelatedconformationallychallengedcytoplasmicproteinsexpressedinCaenorhabditiselegans .We identified 88 suppressors of polyglutamine (polyQ) aggregation, of which 63 modifiers also suppressed aggregation of mutant SOD1G93A. Of these, only 23gene-modifiers suppressed aggregation andrestored animal motility, revealingthat aggregationandtoxicitycanbegeneticallyuncoupled.Nineofthesemodifierswereshowntobeeffectiveinrestoringthe foldingandfunctionofmultipleendogenoustemperature-sensitive(TS)mutantproteins,ofwhichfiveimprovedfoldingin aHSF-1–dependentmanner,byinducingcytoplasmicchaperones.Thistriagescreeningstrategyalsoidentifiedanovelset of PN regulatory components that, by altering metabolic and RNA processing functions, establish alternate cellular environmentsnotgenerallydependentonstressresponseactivationandthatarebroadlyprotectiveagainstmisfoldedand aggregation-proneproteins. Citation:SilvaMC,FoxS,BeamM,Th