SERIES|PersPectivehttps://doi.org/10.1038/s41556-018-0092-5DepartmentofBiochemistryandMolecularBiology,GraduateSchoolandFacultyofMedicine,TheUniversityofTokyo,Tokyo,Japan.e-mail:nmizu@m.u-tokyo.ac.jpItmightcomeasasurprise,buttheterm‘autophagy’wasalreadyinuseinthe1860s—almostacenturybeforethediscoveryofthelysosomebyChristiandeDuvein1955.Atthattime,autophagyreferredtoaconceptthatthehumanbodyhasaself-nourishmentsystem,which,attimesofnutrientdeprivation,permitstheindi-vidualtosurvivebyfeedingoffitself1.ItwasdeDuvewhousedthetermautophagy,in1963,accordingtoitscurrentdefinition:thecellularprocessthroughwhichintracellularmaterialsaredeliveredtothelysosomeorvacuolefordegradation2(Fig.1).Substratesofautophagyincludesolublefactors(forexample,proteins),higher-ordercomplexes(suchas,ribosomesandfluidphasecon-densates)andmembrane-boundorganelles(forexample,mito-chondria)3–5(alsosee‘Howcanautophagybeselective?’below).Extracellularmaterialandportionsoftheplasmamembranecanalsobedegradedinthelysosomebutaredeliveredthroughendo-cytosis,adistinctprocess2.Asautophagycargoesjourneytowardsthelysosomallumen,therearemembranebarriersforhydrophilicmoleculesandlargestructuresthatcannotfreelycrosslipidbilay-ers.Toovercomethesebarriers,threemajortypesofautophagyareused:macroautophagy,microautophagyandchaperone-medi-atedautophagy(CMA)(Fig.2).Inmacroandmicroautophagy,degradationofmembranebarriers(theinnerautophagosomalmembraneandtheintra-luminalvesiclemembrane,respectively)enablesthefinaldegradationofsubstrates,whereasduringCMAsubstrateproteinsdirectlytranslocateacrossthelysosomalmem-branethroughputativepores6,7.AbriefhistoryofautophagyThefieldofautophagyresearchhasgrownexponentially.Molecularmechanismsandphysiologicalfunctionsofautophagyhavebeenrevealedinvariousorganisms.Identificationofautophagygenes.Duringthe1960s–1990s,autophagywasusuallystudiedwithbiochemical,cellphysiologi-calandultrastructuraltechniques(Fig.1).Extensiveinvestigationsoftheregulationofautophagybydepletionofaminoacidsa...
