Autophagy: Molecular Mechanisms and Disease Outcomes

Home , Autophagy, Vojo Deretic

Supplement to Nature Publishing Group Telephone: +1-617-679-7000 Website: www.millennium.com that makeareal difference inthefightagainstcancerbyfollowing itsVision: We Aspire toCure Cancer. lives. Theultimategoalis tofindcures forcancer, butuntilthen, theCompanystrivestodelivermedicines survive. We haveover300projects underwayandmore than17novelorbest-in-classdrugcandidates. range ofcancers. Ourfocusindrugdevelopmentisondiseasepathways thatcancercellsdependonto Millennium operates asTakeda’s GlobalCenterofExcellenceinOncology. The Takeda OncologyCompany. Asawhollyownedandindependentsubsidiary ofTakeda, acquired byTakeda PharmaceuticalCompanyLimitedinMay2008andrenamed Millennium: Millennium Pharmaceuticals,Inc. size, and it can be deconjugated from PEbyasecondAtg4-dependent cleavage. known asGATE16) andGABARAPL3.Atg8(LC3inmammals)helpsdetermineautophagosome Atg8 familymembersinmammalsincludeLC3, GABARAP, GABARAPL1,GABARAPL2(also act asanE3ligaseforAtg8–PEconjugation,andmaydictatethesiteofconjugation. by Atg7(shownas is processed bytheAtg4protease atits Two ubiquitin-likeprotein conjugationsystemsregulate expansion.Atg8 Ubiquitin-like conjugationsystems mATG9 isinitiallylocalizedtothetrans juxtaposed tomitochondria;inmammaliancells, pathway, andapopulationislocatedinreservoirs complex. Inyeast,Atg9transits through thesecretory membranes (thephagophore) bythePtdIns3K and WIPI2,are recruited toPtdIns3P-marked Atg18 anditsmammalianhomologues,WIPI1 the Atg1–Atg13andAtg2–Atg18complexes. of Atg9backtothedonorsitesinvolves Atg23 andAtg27. Retrograde move atio of Atg9tothesitevesicleform expansion. Anterograde movement donor membranes forphagophore puncta, whichprobably markthe detected inmultiplediscrete autophagosome formation.Itis brane Atgprotein required for Atg9 istheprimarytransmem Atg9 transport plasm complex, mitochondriaand/or membran probably byincorporating to formtheautophagosome, ment, thephagophore, expands The initialsequesteringcompart Phagophore expansion by interacting withAtg8(inyeast)andLC3mammals). in yeast and ALFY in mammals) linking the cargo with nascent auto (for example,Atg19,p62,NBR1andNDP52)and/oradaptorsAtg11 to thecargo byaubiquitinligasesuchasparkin.Tags are recognized byreceptors and mitochondria(Atg32inyeastNIXmammals),oraubiquitinmodificationisadded invasive microorganisms. Sometargets comewithabuilt-intag,asprApe1(propeptide) Autophagy canselectivelytarget superfluousordamagedorganelles, specificproteins or Cargo selection CELL MO Millennium’s toppriorityis todevelopandbringmarketnewdrugcandidates thatimprove patients’ Millennium hasarobust developmentpipelineofdrugcandidatesthatare beinginvestigatedinabroad #VI :GPQRJCI[KPOCOOCNU #VI n, thePAS inyeast,requires Atg11, membrane. a /KVQRJCI[KP[GCUV $CEVGTKWO 7D 7D e from theER,Golgi #VI /KVQEJQPFTKQ R R LECU #VI #VI

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5GUVTKP 9+2+ #WVQN[UQUQOG QT415 OGVJ[NCFGPKPG #/2- %NCUU+++2VF+PU- R response; UVRAG,UVradiation resistance-associated gene;Vps, vacuolarprotein sorting;WIPI,WDrepeat domainphosphoinositide-interacting. UNC ULK, ubiquitin; Ub, containing; cysteine-rich and BECLIN 1-interacting domain RUN RUBICON, species; PtdIns3P,3-kinase; PtdIns PtdIns3K, phosphatidylinositol; PtdIns, I; PtdIns 3 aminopeptidase precursor prApe1, phosphatidylethanolamine; PE, PAS,site; BNIP3L); assembly as phagophore known (also NIP3-like X NIX, CALCOCO2); as known (also 52 kDa protein dot nuclear NDP52, gene 1; BRCA1 to next NBR1, complex II; histocompatibility major mATG,MHCII, autophagy-related; mammalian aminopeptidase I; mature mApe1, MAP1LC3); as known (also 3 chain light 1 proteinmicrotubule-associated LC3, glycoprotein 2; membrane associated protein; GABARAPL,GABARAP-like;HMGB1,high-mobility group B1;HSC70,heatshockcognate 70;LAMP2A,lysosome-associated protein 1(alsoknown asZFYVE1);ER,endoplasmicreticulum; ERAD,ER-associateddegradation; GABARAP, BIF1, BAX-interacting factor1;C-terminal,carboxy-terminal;CMA,chaperone-mediated autophagy;DFCP1,doubleFYVEdomain-containing protein 1; coiled-coil myosin/moesin-like interacting BCL-2 1, ATG16L,BECLIN BARKOR); Atg16-like; as yeast known ATG14L,(also Atg14-like yeast autophagy-related; Atg, autophagy 1; 1-regulated BECLIN in molecule activating AMBRA1, WDFY3); ALFY,as known (also FYVE autophagy-linked Abbreviations %NCUU+++2VF+PU- YQTVOCPPKP #VI EQORNGZ+ /COOCNU &(%2 #VI

GUU EQORNGZ+ .-$ #VI %C/-- promise ofallowingustotarget thispathwayfortherapeutic purposes. in recent yearsandisdepictedhere forbothyeastandmammals.Thisknowledgeholdsthe human diseases.Our molecular understandingofautophagyhasincreased exponentially and developmental processes, whereas autophagic dysfunction isassociatedwithvarious invasive microorganisms. Whenproperly regulated, autophagy supportsnormalcellular specific autophagycantarget superfluousordamagedorganelles, protein aggregates or situations, forexampleinresponse tostarvation.However, dependingonthesignal,highly %C β 7D $'%.+0 2 #/$4# .% 2 2 825 .% 9+2+ .% # R 6). microbial infection.Inyeast,theprimaryregulation ofautophagyisnutrientdependent programmes andbyvarioustypesofstress, includingnutrientlimitation,hypoxiaand Autophagy occursatabasallevelbutcanbefurtherinducedduringdevelopmental Induction .% R %CT R .% 7D 7D and is controlled by a complex network of positive and negative pathways. Proteins pathways. negative and positive of network complex a by controlled and is R R .% IQUGNGEVKQP .% 2JCIQRJQT 7D R 7D 7D depicted inpinkandgreen ultimatelyinhibitandstimulate,respectively, the $+( .% EQORNGZ++ %NCUU+++2VF+PU- 2 47$+%10 $'%.+0 activity of the Atg1 kinase complex (the ULK1 and ULK2 complex in activity oftheAtg1kinasecomplex(theULK1andULK2in G 784#) 825 $CEVGTKWO mammals) and,subsequently, autophagy. Theinteractions withtheAtg1 R #WVQRJCIQUQOG kinase complexshownare notnecessarilydirect. TheAtg1kinase .#/2# HQTOCVKQPCPF complex plays a crucial part in autophagy induction and also acts complex playsacrucialpartinautophagyinductionandalsoacts .% R OCVWT #WVQRJCIQUQOG at laterstagesoftheprocess; however, itislikelythatnotall 7D of itsphysiologicalsubstrates havebeenidentified. *5% 7D R .% CVKQP . [UQUQOG receptor andlumenalHSC70,fordegradation. through theactionofLAMP2Amembrane translocated across thelysosomemembrane, unfolded bycytosolicHSC70chaperones and a looselyconservedKFERQconsensusmotifare macroautophagy. Individualproteins thatcontain CMA functionstemporally aftertheinductionof Chaperone-mediated autophagy macroautophagy. Autophagosome formation formation that is involved in some types of formation thatisinvolvedinsometypesof and maturation the omegasome,ascaffoldforphagophore 2 Expansion ofthephagophore intoan GTOGCUG binds PtdIns3Panddirects theformationof autophagosome requires thegeneration the conjugation of LC3 to PE. DFCP1 also the conjugationofLC3toPE.DFCP1also of thephospholipidPtdIns3P. ATG16L andULK1,whichinpartdirect PtdIns3K complex of PtdIns3Precruits WIPI2,alongwith The Vps34complexgenerates PtdIns3P, complex totheER.Thegeneration which mayallowrecruitment of ATG14L targets thePtdIns3K certain Atg components to the certain Atgcomponentstothe The omegasome phagophore. There are multiple BIF1, RUBICONandHMGB1. Vps34 complexes,eachofwhich mammalian cells include AMBRA1, mammalian cellsincludeAMBRA1, contains theVps34lipidkinase, Additional modulatingproteins in the Vps15regulatory kinase complex includes UVRAG. complex includesUVRAG. (p150 inmammals)andAtg6 autolysosome in mammals the autolysosome inmammalsthe During mammals). 1 in (BECLIN during maturation intoan (ATG14L inmammals),whereas Vps34 complexcontainsAtg14 phagophore formation,the γ ‑ 51 -aminobutyric acidreceptor- ‑ phosphate; ROS, reactive oxygen oxygen reactive ROS, phosphate; ‑ like kinase; UPR, unfolded protein unfolded UPR, kinase; like

For the reference list see: http://www.nature.com/nrm/poster *Beneficial ( Autophagy inhealthanddisease Cancer Disease orprocess Ageing Embryogenesis Development Diabetes renal diseases Heart, vascular and Liver disease bowel disease inflammatory Immune response; infection Microbial diseases lysosomal storage Myopathies; diseases Neurodegenerative comments. We thankN.Mizushima forhelpful Acknowledgements 5 microbial adaptations. Levine, B.Autophagy, immunity, and Biol. history ofmacroautophagy. Yang, Z.&Klionsky, D.J.Eatenalive: a clean house. Deretic, V. &Klionsky, D.J.Howcells Further Reading , 527–549(2009)

12 22 1,2 , 814–822 (2010) | Deretic, V.Deretic, (2010) | 814–822 , & 5 3,4 13,14 6,7 ) or harmful ( Sci. Am. 9 15–19 10–12 8 20,21

298 Cell Host Microbe Role ofautophagy* ) roles of autophagy in health and disease. , 74–81 (2008) | (2008) | 74–81 , wasting in progeria Increased levels may lead to muscle and organ and prolong life aggregated macromolecules to increase health Removes damaged organelles and oxidized or Unknown cell death the removal of dead cells during programmed transplacental supply of nutrients; involved in neonates to survive after termination of the Required for embryo implantation; allows Unknown reticulocytes is key to erythrocyte differentiation Removal of mitochondria by mitophagy in autophagy and pancreatic Exposure to free fatty acids can lead to excessive high-fat diet; may affect neutral lipid metabolism function; involved in the response of Basal levels maintain normal islet structure and Can be harmful during reperfusion disease against apoptosis in plaques; prevents glomerular ischaemia and pressure overload; may protect cardiomyocytes and podocytes; protective during Its homeostatic properties are essential to liver damage Excessive autophagic removal of the ER can cause overloads the UPR and ERAD the ER to be removed when protein misfolding Role in organelle homeostasis allows portions of when defective May promote excess inflammatory cytokines homeostasis; counters damaging inflammation T cell maturation and B cell and T cell presentation; regulates naive T cell repertoires, Processes endogenous antigens for MHCII autophagy or use it to promote their own growth Some pathogens have adaptations that counter inflammatory response to microbial products regulates innate immunity and the protective Helps eliminate invasive microorganisms and physiology; excessive levels cause muscle wasting maturation is impeded can compromise cellular Accumulation of autophagosomes when homeostasis dysfunctional organelles and maintain cellular the accumulation of protein aggregates or Removes proteins and organelles to prevent can generate pathology-associated peptides Amyloid precursor protein in autophagosomes mitochondria by mitophagy in neurons; selectively removes damaged Basal levels clear toxic protein aggregates Used by cancer cells for cytoprotection Functions in tumour suppression Nature Cell

autophagy http://www.nature.com/nrm/posters/  Klionsky. Daniel J. designed byVicky Summersbyand copy-edited byAntonyBickenson; Edited byKatharineWrighton; [email protected] [email protected] Contact Information 2011Nature Publishing Group. β s/autophagy -cell death

β -cells to a -cells to a

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Supplementary information to poster | Autophagy: molecular mechanisms and disease outcomes. Daniel J. Klionsky and Vojo Deretic April 2010 (http://www.nature.com/nrm/posters/autophagy)

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