Polyglutaminetractsregulatebeclin1-dependentautophagyAvrahamAshkenazi1,CarlaF.Bento1,ThomasRicketts1,MariellaVicinanza1,FarahSiddiqi1,MarianaPavel1,FerdinandoSquitieri2,MaartenC.Hardenberg1,SaraImarisio1,FionaM.Menzies1,andDavidC.Rubinsztein1,*1DepartmentofMedicalGenetics,CambridgeInstituteforMedicalResearch(CIMR),UniversityofCambridge,Cambridge,UK2IRCCSCasaSollievodellaSofferenza,HuntingtonandRareDiseasesUnit,SanGiovanniRotondo,ItalyAbstractNineneurodegenerativediseasesarecausedbyexpandedpolyglutamine(polyQ)tractsindifferentproteins,likehuntingtininHuntington’sdisease(HD)andataxin-3inspinocerebellarataxiatype3(SCA3)1,2.Age-at-onsetdecreaseswithincreasingpolyglutaminelengthintheseproteinsandthenormallengthisalsopolymorphic3.PolyQexpansionsdrivepathogenesisinthesediseases,asisolatedpolyQtractsaretoxic,andanN-terminalhuntingtinfragmentcomprisingexon1,whichoccursinvivoduetoalternativesplicing4,causestoxicity.Whilesuchmutantproteinsareaggregate-prone5,toxicityisalsoassociatedwithsolubleformsoftheproteins6.ThefunctionofthepolyQtractsinmanynormal/wild-typecytoplasmicproteinsisunclear.Onesuchproteinisthedeubiquitinatingenzymeataxin37,8,whichiswidelyexpressedinthebrain9,10.HereweshowthatthepolyQdomaininwild-typeataxin-3enablesitsinteractionwithbeclin1,akeyautophagyinitiator11.Thisinteractionallowsthedeubiquitinaseactivityofataxin-3toprotectbeclin1fromproteasome-mediateddegradationandthusenablesautophagy.Starvation-inducedautophagy,whichisregulatedbybeclin1,wasparticularlyinhibitedinataxin-3-depletedhumancell-lines,primaryneuronsandin-vivo.Thisactivityofataxin-3anditsinteractionwithbeclin1mediatedbyitspolyQdomainwascompetedbyothersolubleproteinswithpolyQtractsinalength-dependentfashion.Thisresultedinimpairedstarvation-inducedautophagyincellsexpressingmutanthuntingtinexon1,whichwasalsorecapitulatedinthebrainofHDmousemodelandinpatientcells.AsimilarphenomenonwasalsoseenwithotherpolyQdiseaseproteins,includingmutantataxin-3itself.Ourdatathusdescribeaspecificfunctionforawild-t...
