Abstract
Autophagy is a highly conserved cellular degradation process in which portions of cytosol and organelles are sequestered into a double-membrane vesicle, an autophagosome, and delivered into a degradative organelle, the vacuole/lysosome, for breakdown and eventual recycling of the resulting macromolecules. This process relieves the cell from various stress conditions. Autophagy plays a critical role during cellular development and differentiation, functions in tumor suppression, and may be linked to life span extension. Autophagy also has diverse roles in innate and adaptive immunity, such as resistance to pathogen invasion. Substantial progress has been made in the identification of many autophagy-related (ATG) genes that are essential to drive this cellular process, including both selective and nonselective types of autophagy. Identification of the ATG genes in yeast, and the finding of orthologs in other organisms, reveals the conservation of the autophagic machinery in all eukaryotes. Here, we summarize our current knowledge about the machinery and molecular mechanism of autophagy.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Abeliovich H, Zhang C. Dunn WA Jr, Shokat KM, Klinosy DJ (2003) Chemical genetic analysis of Apgl reveals a non-kinase role in the induction of autophagy. Mol Biol Cell 14:477–490.
Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, Ogier-Denis E (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276:35243–35246
Atlashkin V, Kreykenbohm V, Eskelinen E-L, Wenzel D, Fayyazi A, Fischer von Mollard G (2003) Deletion of the SNARE vti1b in mice results in the loss of a single SNARE partner, syntaxin 8. Mol Cell Biol 23:5198–5207
Baba M, Osumi M, Scott SV, Klionsky DJ, Ohsumi Y (1997) Two distinct pathways for targeting proteins from the cytoplasm to the vacuole/lysosome. J Cell Biol 139:1687–1695
Bellu AR, Komori M, van der Klei IJ, Kiel JAKW, Veenhuis M (2001) Peroxisome biogenesis and selective degradation converge at Pex14p. J Biol Chem 276:44570–44574
Berg TO, Fengsrud M, Stromhaug PE, Berg T, Seglen PO (1998) Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J Biol Chem 273:21883–21892
Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Øvervatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614
Budovskaya YV, Stephan JS, Reggiori F, Klionsky DJ, Herman PK (2004) The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J Biol Chem 279:20663–20671
Budovskaya YV, Stephan JS, Deminoff SJ, Herman PK (2005) An evolutionary proteomics approach identifies substrates of the cAMP-dependent protein kinase. Proc Natl Acad Sci USA 102:13933–13938
Carrera AC (2004) TOR signaling in mammals. J Cell Sci 117:4615–4616
Carroll AS, O’Shea EK (2002) Pho85 and signaling environmental conditions. Trends Biochem Sci 27:87–93
Chan EYW, Kir S, Tooze SA (2007) siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 282:25464–25474
Chang CY, Huang W-P (2007) Atg19 mediates a dual interaction cargo sorting mechanism in selective autophagy. Mol Biol Cell 18:919–929
Cheong H, Nair U, Geng J, Klionsky DJ (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19:668–681
De Virgilio C, Loewith R (2006) Cell growth control: little eukaryotes make big contributions. Oncogene 25:6392–6415
Ellson CD, Andrews S, Stephens LR, Hawkins PT (2002) The PX domain: a new phosphoinositide-binding module. J Cell Sci 115:1099–1105
Epple UD, Suriapranata I, Eskelinen E-L, Thumm M (2001) Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J Bacteriol 183:5942–5955.
Epple UD, Eskelinen E-L, Thumm M (2003) Intravacuolar membrane lysis in Saccharomyces cerevisiae. Does vacuolar targeting of Cvt17/Aut5p affect its function? J Biol Chem 278:7810–7821
Farre JC, Manjithaya R, Mathewson RD, Subramani S (2008) PpAtg30 tags peroxisomes for turnover by selective autophagy. Dev Cell 14:365–376
Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrance biogenesis in autophagy. Mol Biol Cell 19:2092–2100.
Furuta S, Hidaka E, Ogata A, Yokota S, Kamata T (2004) Ras is involved in the negative control of autophagy through the class I PI3-kinase. Oncogene 23:3898–3904
Guan J, Stromhaug PE, George MD, Habibzadegah-Tari P, Bevan A, Dunn WA Jr, Klionsky DJ (2001) Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. Mol Biol Cell 12:3821–3838
Gunkel K, van der Klei IJ, Barth G, Veenhuis M (1999) Selective peroxisome degradation in Yarrowia lipolytica after a shift of cells from acetate/oleate/ethylamine into glucose/ammonium sulfate-containing media. FEBS Lett 451:1–4
Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–766
Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y (2007) The Atg12–Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282:37298–37302
Hanaoka H, Noda T, Shirano Y, Kato T, Hayashi H, Shibata D, Tabata S, Ohsumi Y (2002) Leaf senescence and starvation-induced chlorosis are accelerated by the disruption of an Arabidopsis autophagy gene. Plant Physiol 129:1181–1193
Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181:497–510
He C, Song H, Yorimitsu T, Monastyrska I, Yen W-L, Legakis JE, Klionsky DJ (2006) Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast. J Cell Biol 175:925–935
Hemelaar J, Lelyveld VS, Kessler BM, Ploegh HL (2003) A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L. J Biol Chem 278:51841–51850
Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450
Høyer-Hansen M, Jäättelä M (2007) AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 3:381–383
Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle 6:1837–1849
Huang W-P, Scott SV, Kim J, Klionsky DJ (2000) The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem 275:5845–5851
Hutchins MU, Klionsky DJ (2001) Vacuolar localization of oligomeric α-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J Biol Chem 276:20491–20498
Hutchins MU, Veenhuis M, Klionsky DJ (1999) Peroxisome degradation in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway. J Cell Sci 112 (Pt 22):4079–4087
Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y (2000) A ubiquitin-like system mediates protein lipidation. Nature. 408:488–492
Ichimura Y, Imamura Y, Emoto K, Umeda M, Noda T, Ohsumi Y (2004) In vivo and in vitro reconstitution of Atg8 conjugation essential for autophagy. J Biol Chem 279:40584–40592
Iwata J, Ezaki J, Komatsu M, Yokota S, Ueno T, Tanida I, Chiba T, Tanaka K, Kominami E (2006) Excess peroxisomes are degraded by autophagic machinery in mammals. J Biol Chem 281:4035–4041
Jacinto E, Hall MN (2003) Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 4:117–126
Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen E-L (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848
Jeffries TR, Dove SK, Michell RH, Parker PJ (2004) PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49. Mol Biol Cell 15:2652–2663
Kabeya Y, Kamada Y, Baba M, Takikawa H, Sasaki M, Ohsumi Y (2005) Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16:2544–2553
Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728
Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T (2004) LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 117:2805–2812
Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150:1507–1513
Kawamata T, Kamada Y, Kabeya Y, Sekito T, Ohsumi Y (2008) Organization of the pre-autophagosomal structure responsible for autophagosome formation. Mol Biol Cell 19:2039–2050
Kihara A, Noda T, Ishihara N, Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152:519–530
Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253
Kim J, Scott SV, Oda MN, Klionsky DJ (1997) Transport of a large oligomeric protein by the cytoplasm to vacuole protein targeting pathway. J Cell Biol 137:609–618
Kim J, Kamada Y, Stromhaug PE, Guan J, Hefner-Gravink A, Baba M, Scott SV, Ohsumi Y, Dunn WA Jr, Klionsky DJ (2001) Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. J Cell Biol 153:381–396
Kim J, Huang W-P, Stromhaug PE, Klionsky DJ (2002) Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J Biol Chem 277:763–773
Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T, Ohsumi Y (1999) Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147:435–446
Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y (2000) The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 151:263–276
Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18
Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5:539–545
Klionsky DJ, Cueva R, Yaver DS (1992) Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J Cell Biol 119:287–299
Klionsky DJ, Meijer AJ, Codogno P (2005) Autophagy and p70S6 kinase. Autophagy 1:59–61
Komatsu M, Ueno T, Waguri S, Uchiyama Y, Kominami E, Tanaka K (2007a) Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. Cell Death Differ 14:887–894
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K (2007b) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163
Kraft C, Deplazes A, Sohrmann M, Peter M (2008) Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat Cell Biol 10:602–610
Kubota H, Obata T, Ota K, Sasaki T, Ito T (2003) Rapamycin-induced translational derepression of GCN4 mRNA involves a novel mechanism for activation of the eIF2α kinase GCN2. J Biol Chem 278:20457–20460
Kuma A, Mizushima N, Ishihara N, Ohsumi Y (2002) Formation of the approximately 350-kDa Apg12–Apg5·Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J Biol Chem 277:18619–18625
Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036
Kundu M, Lindsten T, Yang CY, Wu J, Zhao F, Zhang J, Selak MA, Ney PA, Thompson CB (2008) Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112:1493–1502
Legakis JE, Yen W-L, Klionsky DJ (2007) A cycling protein complex required for selective autophagy. Autophagy 3:422–432
Levine B, Deretic V (2007) Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 7:767–777
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477
Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB (2007) The energy sensing LKB1–AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218–224
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676
Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468
Martinez E, Jimenez MA, Segui-Real B, Vandekerckhove J, Sandoval IV (1997) Folding of the presequence of yeast pAPI into an amphipathic helix determines transport of the protein from the cytosol to the vacuole. J Mol Biol 267:1124–1138
Massey A, Kiffin R, Cuervo AM (2004) Pathophysiology of chaperone-mediated autophagy. Int J Biochem Cell Biol 36:2420–2434
Matsuura A, Tsukada M, Wada Y, Ohsumi Y (1997) Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192:245–250.
Mavrakis M, Lippincott-Schwartz J, Stratakis CA, Bossis I (2006) Depletion of type IA regulatory subunit (RIα) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Hum Mol Genet 15:2962–2971
Meijer AJ, Codogno P (2006) Signalling and autophagy regulation in health, aging and disease. Mol Aspects Med 27:411–425
Meléndez A, Tallóczy Z, Seaman M, Eskelinen E-L, Hall DH, Levine B (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301:1387–1391
Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ (2006) AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281:34870–34879
Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (1998a) A protein conjugation system essential for autophagy. Nature 395:395–398
Mizushima N, Sugita H, Yoshimori T, Ohsumi Y (1998b) A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 273:33889–33892
Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T (2001) Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152:657–668
Mizushima N, Yoshimori T, Ohsumi Y (2002) Mouse Apg10 as an Apg12-conjugating enzyme: analysis by the conjugation-mediated yeast two-hybrid method. FEBS Lett 532:450–454
Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, Natsume T, Ohsumi Y, Yoshimori T (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116:1679–88
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075
Monastyrska I, Shintani T, Klionsky DJ, Reggiori F (2006) Atg11 directs autophagosome cargoes to the PAS along actin cables. Autophagy 2:119–121
Monastyrska I, He C, Geng J, Hoppe AD, Li Z, Klionsky DJ (2008) Arp2 links autophagic machinery with the actin cytoskeleton. Mol Biol Cell 19:1962–1975
Nair U, Klionsky DJ (2005) Molecular mechanisms and regulation of specific and nonspecific autophagy pathways in yeast. J Biol Chem 280:41785–41788
Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T (2004) Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040
Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165–178
Nice DC, Sato TK, Stromhaug PE, Emr SD, Klionsky DJ (2002) Cooperative binding of the cytoplasm to vacuole targeting pathway proteins, Cvt13 and Cvt20, to phosphatidylinositol 3-phosphate at the pre-autophagosomal structure is required for selective autophagy. J Biol Chem 277:30198–30207
Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 102:14238–14243
Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273:3963–3966
Noda T, Kim J, Huang W-P, Baba M, Tokunaga C, Ohsumi Y, Klionsky DJ (2000) Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J Cell Biol 148:465–480
Noda T, Suzuki K, Ohsumi Y (2002) Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol 12:231–235
Obara K, Sekito T, Ohsumi Y (2006) Assortment of phosphatidylinositol 3-kinase complexes: Atg14p directs association of complex I to the pre-autophagosomal structure in Saccharomyces cerevisiae. Mol Biol Cell 17:1527–1539
Oda MN, Scott SV, Hefner-Gravink A, Caffarelli AD, Klionsky DJ (1996) Identification of a cytoplasm to vacuole targeting determinant in aminopeptidase I. J Cell Biol 132:999–1010
Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C (2005) Escape of intracellular Shigella from autophagy. Science 307:727–731
Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2:211–216
Onodera J, Ohsumi Y (2004) Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae. J Biol Chem 279:16071–16076
Orvedahl A, Levine B (2008) Viral evasion of autophagy. Autophagy 4:280–285
Otto GP, Wu MY, Kazgan N, Anderson OR, Kessin RH (2004) Dictyostelium macroautophagy mutants vary in the severity of their developmental defects. J Biol Chem 279:15621–15629
Panaretou C, Domin J, Cockcroft S, Waterfield MD (1997) Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150·Ptdins 3-kinase complex. J Biol Chem 272:2477–2485
Paz Y, Elazar Z, Fass D (2000) Structure of GATE-16, membrane transport modulator and mammalian ortholog of autophagocytosis factor Aut7p. J Biol Chem 275:25445–25450
Reggiori F, Klionsky DJ (2002) Autophagy in the eukaryotic cell. Eukaryot Cell 1:11–21
Reggiori F, Monastyrska I, Shintani T, Klionsky DJ (2005a) The actin cytoskeleton is required for selective types of autophagy, but not nonspecific autophagy, in the yeast Saccharomyces cerevisiae. Mol Biol Cell 16:5843–5856
Reggiori F, Shintani T, Nair U, Klionsky DJ (2005b) Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts. Autophagy 1:101–109
Reggiori F, Tucker KA, Stromhaug PE, Klionsky DJ (2004a) The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev Cell 6:79–90
Reggiori F, Wang C-W, Nair U, Shintani T, Abeliovich H, Klionsky DJ (2004b) Early stages of the secretory pathway, but not endosomes, are required for Cvt vesicle and autophagosome assembly in Saccharomyces cerevisiae. Mol Biol Cell 15:2189–2204
Russnak R, Konczal D, McIntire SL (2001) A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J Biol Chem 276:23849–23857
Sagne C, Agulhon C, Ravassard P, Darmon M, Hamon M, El Mestikawy S, Gasnier B, Giros B (2001) Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc Natl Acad Sci USA 98:7206–7211
Sakai Y, Oku M, van der Klei IJ, Kiel JAKW (2006) Pexophagy: autophagic degradation of peroxisomes. Biochim Biophys Acta 1763:1767–1775
Schmelzle T, Beck T, Martin DE, Hall MN (2004) Activation of the RAS/cyclic AMP pathway suppresses a TOR deficiency in yeast. Mol Cell Biol 24:338–351
Scott RC, Schuldiner O, Neufeld TP (2004) Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 7:167–178
Scott RC, Juhasz G, Neufeld TP (2007) Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol 17:1–11
Scott SV, Baba M, Ohsumi Y, Klionsky DJ (1997) Aminopeptidase I is targeted to the vacuole by a nonclassical vesicular mechanism. J Cell Biol 138:37–44
Scott SV, Guan J, Hutchins MU, Kim J, Klionsky DJ (2001) Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway. Mol Cell 7:1131–1141
Seglen PO, Gordon PB, Holen I (1990) Non-selective autophagy. Semin Cell Biol 1:441–448
Shintani T, Klionsky DJ (2004a) Autophagy in health and disease: a double-edged sword. Science 306:990–995
Shintani T, Klionsky DJ (2004b) Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway. J Biol Chem 279:29889–29894
Shintani T, Mizushima N, Ogawa Y, Matsuura A, Noda T, Ohsumi Y (1999) Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. EMBO J 18:5234–5241
Shintani T, Huang W-P, Stromhaug PE, Klionsky DJ (2002) Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev Cell 3:825–837
Stack JH, DeWald DB, Takegawa K, Emr SD (1995) Vesicle-mediated protein transport: regulatory interactions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacuole in yeast. J Cell Biol 129:321–334
Stenmark H, Aasland R, Driscoll PC (2002) The phosphatidylinositol 3-phosphate-binding FYVE finger. FEBS Lett 513:77–84
Stromhaug PE, Reggiori F, Guan J, Wang C-W, Klionsky DJ (2004) Atg21 is a phosphoinositide binding protein required for efficient lipidation and localization of Atg8 during uptake of aminopeptidase I by selective autophagy. Mol Biol Cell 15:3553–3566
Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y (2001) The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20:5971–5981
Suzuki K, Kubota Y, Sekito T, Ohsumi Y (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12:209–218
Suzuki NN, Yoshimoto K, Fujioka Y, Ohsumi Y, Inagaki F (2005) The crystal structure of plant Atg12 and its biological implication in autophagy. Autophagy 1:119–126
Tallóczy Z, Jiang W, Virgin HW IV, Leib DA, Scheuner D, Kaufman RJ, Eskelinen E-L, Levine B (2002) Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway. Proc Natl Acad Sci USA 99:190–195
Tanida I, Mizushima N, Kiyooka M, Ohsumi M, Ueno T, Ohsumi Y, Kominami E (1999) Apg7p/Cvt2p: a novel protein-activating enzyme essential for autophagy. Mol Biol Cell 10:1367–1379
Tanida I, Tanida-Miyake E, Komatsu M, Ueno T, Kominami E (2002) Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p. J Biol Chem 277:13739–13744
Tanida I, Komatsu M, Ueno T, Kominami E (2003) GATE-16 and GABARAP are authentic modifiers mediated by Apg7 and Apg3. Biochem Biophys Res Commun 300:637–644
Tanida I, Sou YS, Minematsu-Ikeguchi N, Ueno T, Kominami E (2006) Atg8L/Apg8L is the fourth mammalian modifier of mammalian Atg8 conjugation mediated by human Atg4B, Atg7 and Atg3. FEBS J 273:2553–2562
Teter SA, Eggerton KP, Scott SV, Kim J, Fischer AM, Klionsky DJ (2001) Degradation of lipid vesicles in the yeast vacuole requires function of Cvt17, a putative lipase. J Biol Chem 276:2083–2087
Thevelein JM, de Winde JH (1999) Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol 33:904–918
Tooze J, Hollinshead M, Ludwig T, Howell K, Hoflack B, Kern H (1990) In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. J Cell Biol 111:329–345
Tuttle DL, Lewin AS, Dunn WA Jr (1993) Selective autophagy of peroxisomes in methylotrophic yeasts. Eur J Cell Biol 60:283–290
Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26:663–674
Veenhuis M, Douma A, Harder W, Osumi M (1983) Degradation and turnover of peroxisomes in the yeast Hansenula polymorpha induced by selective inactivation of peroxisomal enzymes. Arch Microbiol 134:193–203
Wang C-W, Klionsky DJ (2003) The molecular mechanism of autophagy. Mol Med 9:65–76
Wang C-W, Kim J, Huang W-P, Abeliovich H, Stromhaug PE, Dunn WA Jr, Klionsky DJ (2001a) Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. J Biol Chem 276:30442–30451
Wang C-W, Stromhaug PE, Kauffman EJ, Weisman LS, Klionsky DJ (2003) Yeast homotypic vacuole fusion requires the Ccz1-Mon1 complex during the tethering/docking stage. J Cell Biol 163:973–985
Wang Z, Wilson WA, Fujino MA, Roach PJ (2001b) Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol 21:5742–5752
Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9:1102–1109
Xie Z, Nair U, Klionsky DJ (2008) Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell 19:3290–3298
Yamada T, Carson AR, Caniggia I, Umebayashi K, Yoshimori T, Nakabayashi K, Scherer SW (2005) Endothelial nitric-oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast. J Biol Chem 280:18283–18290
Yan J, Kuroyanagi H, Kuroiwa A, Matsuda Y, Tokumitsu H, Tomoda T, Shirasawa T, Muramatsu M (1998) Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. Biochem Biophys Res Commun 246:222–227
Yan J, Kuroyanagi H, Tomemori T, Okazaki N, Asato K, Matsuda Y, Suzuki Y, Ohshima Y, Mitani S, Masuho Y, Shirasawa T, Muramatsu M (1999) Mouse ULK2, a novel member of the UNC-51-like protein kinases: unique features of functional domains. Oncogene 18:5850–5859
Yang Z, Huang J, Geng J, Nair U, Klionsky DJ (2006) Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 17:5094–5104
Yen W-L, Legakis JE, Nair U, Klionsky DJ (2007) Atg27 is required for autophagy-dependent cycling of Atg9. Mol Biol Cell 18:581–593
Yorimitsu T, Klionsky DJ (2005a) Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway. Mol Biol Cell 16:1593–1605
Yorimitsu T, Klionsky DJ (2005b) Autophagy: molecular machinery for self-eating. Cell Death Differ 12 Suppl 2:1542–1552
Yorimitsu T, Zaman S, Broach JR, Klionsky DJ (2007) Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18:4180–4189
Yorimitsu T, He C, Wang K, Klionsky DJ (2009) Tap42-associated protein phosphatase type 2A negatively regulates induction of autophagy. Autophagy 5:in press
Young ARJ, Chan EYW, Hu XW, Köchl R, Crawshaw SG, High S, Hailey DW, Lippincott-Schwartz J, Tooze SA (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119:3888–3900
Zurita-Martinez SA, Cardenas ME (2005) Tor and cyclic AMP-protein kinase A: two parallel pathways regulating expression of genes required for cell growth. Eukaryot Cell 4:63–71
Acknowledgments
This work was supported by National Institutes of Health Public Health Service grant GM53396 to D.J.K.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Yang, Z., Klionsky, D.J. (2009). An Overview of the Molecular Mechanism of Autophagy. In: Levine, B., Yoshimori, T., Deretic, V. (eds) Autophagy in Infection and Immunity. Current Topics in Microbiology and Immunology, vol 335. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00302-8_1
Download citation
DOI: https://doi.org/10.1007/978-3-642-00302-8_1
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-00301-1
Online ISBN: 978-3-642-00302-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)