MechanismsofAutophagyInitiationJamesH.Hurley*andLindseyN.YoungDepartmentofMolecularandCellBiologyandCaliforniaInstituteofQuantitativeBiosciences,UniversityofCalifornia,Berkeley,Berkeley,UnitedStates;andMolecularBiophysicsandIntegratedBioimagingDivision,LawrenceBerkeleyNationalLaboratory,Berkeley,UnitedStatesAbstractAutophagyistheprocessofcellularself-eatingbyadouble-membraneorganelle,theautophagosome.Arangeofsignalingprocessesconvergeontwoproteincomplexestoinitiateautophagy:theULK1proteinkinasecomplexandthePI3KC3-C1lipidkinasecomplex.Some90%ofthemassoftheselargeproteincomplexesconsistsonnon-catalyticdomainsandsubunits,andtheULK1complexhasessentialnon-catalyticactivities.Structuralstudiesofthesecomplexeshaveshedincreasinglightontheregulationoftheircatalyticandnon-catalyticactivitiesinautophagyinitiation.TheautophagosomeisthoughttonucleatefromvesiclescontainingtheintegralmembraneproteinAtg9,COPIIvesicles,andpossiblyothersources.Inthewakeofreconstitutionandsuperresolutionimagingstudies,wearebeginningtounderstandhowtheULK1andPI3KC3-C1complexesmightcoordinatethenucleationandfusionofAtg9andCOPIIvesiclesatthestartofautophagosomebiogenesis.Keywordsvesicle;membraneremodeling;tetheringcomplex;membranefusion;nanoscalebiology;ULK1;Atg1;Vps34;phosphatidylinositol3-kinase;COPIIIntroductionMacroautophagy(hereafter“autophagy”)isthemainmechanismusedbyeukaryoticcellstodegradecargoesthatarelargerthanindividualproteins.Itisalsothemainmechanismforeukaryoticcellstoreplenishpoolsofbiosyntheticprecursorsandenergysourcesbyrecyclingcytosoliccontentsduringstarvation.Boththeprocessofautophagyanditsmachineryisconservedfromyeasts(S.cerevisiaeandS.pombe)(1)tomammals(2).Autophagycanbeeitherselectiveornon-selective(“bulk”).Selectiveautophagyremovesandrecyclesharmfulorsimplyunneededmaterialsfromthecell.Theseincludeproteinaggregates,damagedmitochondria,unneededperoxisomes,excessribosomes,ERandendosomes,lipiddroplets,andintracellularpathogens(3,4).Failuretocontroltheaccumulationofanyofthesetype...
