ReviewEmergingMechanismsinInitiatingandTerminatingAutophagyManuelaAntonioli,1,2MartinaDiRienzo,1,3MauroPiacentini,1,3andGianMariaFimia1,4,*Autophagyisamajordegradativeprocessactivatedinarapidandtransientmannertocopewithstressconditions.Whetherautophagyisbeneficialordetrimentaldependsupontherateofinductionandtheappropriatenessoftheduration.Alterationsinbothautophagyinitiationandterminationpredis-posethecelltodeath,andaffecttheexecutionofotherinducibleprocessessuchasinflammation.Inthisreviewwediscusshowstresssignalingpath-waysdynamicallycontroltheactivityoftheautophagymachinerybymediat-ingpost-translationalmodificationsandregulatoryproteininteractions.Inparticular,wehighlighttheemergingroleofTRIMandCULLINfamiliesofubiquitinligaseswhichplayoppositerolesintheautophagyresponsebypromotingorinhibiting,respectively,theactivityoftheautophagyinitiationcomplex.Autophagy–ATightlyRegulatedResponseToStressMacroautophagy,hereafterreferredasautophagy(seeGlossary),protectscellsfromstress-induceddamagebyengulfingnon-functionalcellularcomponentsintodouble-membranevesiclescalledautophagosomesanddeliveringthemtothelysosomefordegradation[1].Bythismechanism,italsomaintainsanappropriateamountof‘buildingelements’toberecycledformacromolecularsynthesisandenergyproductionwhenexternalnutrientsupplyislimited[1].Dysregulatedautophagyisassociatedwithseveralpathologicalconditions[2].Ontheonehand,defectiveautophagyleadstotheaccumulationofproteinaggregatesordysfunctionalorganellesthatpredisposetoneurodegeneration,musculardystrophy,andmetabolicsyndromes[1,3].ImpairmentsinautophagyarealsoassociatedwithincreasedinflammationandthedevelopmentofautoimmunepathologiessuchasCrohn'sdisease[4].Thisisoftencoupledwithaccumulationofreactiveoxygenspecies(ROS),whichcanalsocausegenomicalterationsthatleadtotumorigenesis[1].Ontheotherhand,anunrestrainedresponseturnsautophagyintoacelldeathprocessasaresultofexcessiveself-digestion.Damageinducedbyexcessiveautophagyisobservedinmyocardialandcerebralischemia[5].Acrucia...
