Molecular machinery required for autophagy and the cytoplasm to vacuole targeting (Cvt) pathway in S. cerevisiae

Current Opinion in Cell Biology

Volumn 14, Issue 4, 2002, Pages 468-475

  Khalfan, Waheeda A ^a   Klionsky, Daniel J ^a  

^a UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHATIDYLINOSITOL 3 KINASE; SACCHAROMYCES CEREVISIAE PROTEIN; AMINOPEPTIDASE I; GENE PRODUCT; HYDROLASE; LIPID; PROTEIN APG1; PROTEIN SERINE THREONINE KINASE; TARGET OF RAPAMYCIN KINASE; UNCLASSIFIED DRUG;

AUTOPHAGY; BIOLOGICAL MODEL; CELL VACUOLE; CYTOPLASM; ENZYMOLOGY; FORECASTING; METABOLISM; REVIEW; SACCHAROMYCES CEREVISIAE; TRANSPORT AT THE CELLULAR LEVEL; CONJUGATION; DEGRADATION; LIPID METABOLISM; MEMBRANE; MOLECULAR MECHANICS; NONHUMAN; NUTRIENT; PRIORITY JOURNAL; PROTEIN TRANSPORT; RECYCLING; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; STARVATION; YEAST;

1-PHOSPHATIDYLINOSITOL 3-KINASE; AUTOPHAGY; BIOLOGICAL TRANSPORT; CYTOPLASM; FORECASTING; MODELS, BIOLOGICAL; SACCHAROMYCES CEREVISIAE; SACCHAROMYCES CEREVISIAE PROTEINS; VACUOLES;

SACCHAROMYCES; SACCHAROMYCES CEREVISIAE;

EID: 0036702197     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(02)00343-5     Document Type: Review

References (67)

1. Abeliovich H., Klionsky D.J. Autophagy in yeast: mechanistic insights and physiological function. Microbiol Mol Biol Rev. 65:2001;463-479.
2. Kim J., Klionsky D.J. Autophagy, cytoplasm to vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem. 69:2000;303-342.
3. Klionsky D.J., Ohsumi Y. Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol. 15:1999;1-32.
4. Klionsky D.J., Emr S.D. Autophagy as a regulated pathway of cellular degradation. Science. 290:2000;1717-1721.
5. Schulte-Hermann R., Bursch W., Grasl-Kraupp B., Marian B., Torok L., Kahl-Rainer P., Ellinger A. Concepts of cell death and application to carcinogenesis. Toxicol Pathol. 25:1997;89-93.
6. Nishino I., Fu J., Tanji K., Yamada T., Shimojo S., Koori T., Mora M., Riggs J.E., Oh S.J., Koga Y., et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 406:2000;906-910.
7. Tanaka Y., Guhde G., Suter A., Eskelinen E.L., Hartmann D., Lullmann-Rauch R., Janssen P.M., Blanz J., von Figura K., Saftig P. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature. 406:2000;902-906.
8. Kegel K.B., Kim M., Sapp E., McIntyre C., Castano J.G., Aronin N., DiFiglia M. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci. 20:2000;7268-7278.
9. Noda T., Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 273:1998;3963-3966.
10. Schmelzle T., Hall M.N. TOR, a central controller of cell growth. Cell. 103:2000;253-262.
11. Raught B., Gingras A.C., Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA. 98:2001;7037-7044.
12. Kamada Y., Funakoshi T., Shintani T., Nagano K., Ohsumi M., Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 150:2000;1507-1513. This paper, together with Scott et al. (2000) [13•], lays important groundwork on the molecular basis of autophagy induction. Nutrient-based changes in Tor signaling are shown to regulate Apg13-Apg1 complex formation and the invitro kinase activity of Apg1. Also, Apg1 is shown to physically interact with autophagy and cytoplasm to vacuole targeting (Cvt)-specific components, suggesting that different Apg1-containing complexes drive autophagy and the Cvt pathway.
13. Scott S.V., Nice D.C. III, Nau J.J., Weisman L.S., Kamada Y., Keizer Gunnink I., Funakoshi T., Veenhuis M., Ohsumi Y., Klionsky D.J. Apg13p and Vac8p are part of a complex of phosphoproteins that are required for cytoplasm to vacuole targeting. J Biol Chem. 275:2000;25840-25849. The authors show nutrient-dependent regulation of Apg13 phosphorylation and physical interaction of Apg13 with a Cvt-pathway-specific component Vac8. On the basis of these findings, the authors propose that Apg13 and Vac8 are part of a protein complex that regulates conversion between autophagy and the Cvt pathway.
14. Matsuura A., Tsukada M., Wada Y., Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene. 192:1997;245-250.
15. Funakoshi T., Matsuura A., Noda T., Ohsumi Y. Analyses of APG13 gene involved in autophagy in yeast, Saccharomyces cerevisiae. Gene. 192:1997;207-213.
16. Scott S.V., Hefner-Gravink A., Morano K.A., Noda T., Ohsumi Y., Klionsky D.J. Cytoplasm to vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole. Proc Natl Acad Sci USA. 93:1996;12304-12308.
17. Kim J., Kamada Y., Stromhaug P.E., Guan J., Hefner-Gravink A., Baba M., Scott S.V., Ohsumi Y., Dunn W.A. Jr, Klionsky D.J. Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. J Cell Biol. 153:2001;381-396. The authors show that S. cerevisiae Cvt9 is a peripheral membrane protein required primarily for Cvt vesicle formation and pexophagy. The Pichia pastoris homologue of CVT9, GSA9, is shown to be important mainly for glucose-induced pexophagy. Cvt9 localizes to the membranous perivacuolar site identified in subsequent work to contain many other autophagy proteins. Localization to this site and physical interaction with Apg1 kinase suggests the protein is involved in an early step in Cvt vesicle formation. Gsa9 localizes to perivacuolar regions that contact peroxisomes, suggesting it might help to specifically tether peroxisomes to the vacuole during micropexophagy.
18. Ishihara N., Hamasaki M., Yokota S., Suzuki K., Kamada Y., Kihara A., Yoshimori T., Noda T., Ohsumi Y. Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol Biol Cell. 12:2001;3690-3702.
19. Suzuki K., Kirisako T., Kamada Y., Mizushima N., Noda T., Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20:2001;5971-5981. Using fluorescent-protein tagging, the signaling protein Apg1, and conjugation machinery-related proteins Apg5 and Apg16, are shown to co-localize to a novel perivacuolar structure. Aut7 can be traced to the vacuole, establishing the functional importance of the structure. Significantly, the integral membrane protein Apg9 and members of the Vps34 phosphatidylinositol 3-kinase complex are implicated in localizing the conjugation machinery to this site.
20. Kim J., Huang W.P., Stromhaug P.E., Klionsky D.J. Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J Biol Chem. 277:2002;763-773. Using fluorescent protein tagging, density gradients and affinity isolation, the authors show that autophagy and Cvt-specific components required for vesicle formation co-localize to a novel dot structure at the vacuole edge. This structure, originally defined by Cvt9 localization, contains Cvt19, Apg1p, the Vps34 phosphatidylinositol 3-kinase complex member Apg14, and the conjugation components Apg5 and Apg12. Aut7, an autophagosomal marker, can be traced from the perivacuolar site into the vacuole lumen, suggesting that this compartment is physiologically relevant and might be the initiation site for autophagosome and Cvt vesicle nucleation/formation.
21. Abeliovich H., Darsow T., Emr S.D. Cytoplasm to vacuole trafficking of aminopeptidase I requires a t-SNARE-Sec1p complex composed of Tlg2p and Vps45p. EMBO J. 18:1999;6005-6016.
22. Kihara A., Noda T., Ishihara N., Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 152:2001;519-530. This paper shows that Vps34, a yeast phosphatidylinositol (PI) 3-kinase, exists in two different protein complexes, each containing a protein that functions specifically in Prc1 sorting or the autophagy/Cvt pathways. Thus, it is likely that PI 3-kinase is involved in multiple membrane-trafficking events.
23. Petiot A., Ogier-Denis E., Blommaart E.F., Meijer A.J., Codogno P. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem. 275:2000;992-998.
24. Abeliovich H., Dunn W.A. Jr, Kim J., Klionsky D.J. Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. J Cell Biol. 151:2000;1025-1034. This study of the requirements for autophagy induction leads to a useful two-step model for autophagosome formation: a signaling-based inductive/nucleation step and a protein-synthesis-dependent vesicle-expansion step involving at least one structural component of vesicles, Aut7.
25. Scott S.V., Guan J., Hutchins M.U., Kim J., Klionsky D.J. Cvt19 is a receptor for the cytoplasm to vacuole targeting pathway. Mol Cell. 7:2001;1131-1141. Cvt19, originally identified ina two-hybrid screen, is shown to be a peripheral membrane protein that directly binds precursor aminopeptidase I (prApe 1) and localizes to a perivacoular compartment. Cvt19 is important for prApe 1 targeting via both the cytoplasm to a vacoule targeting and autophagy pathways, and is most likely delivered to the vacoule with prApe 1and then rapidly degraded. These observations argued that Cvt19 functions either as a receptor or an adapter for a prApe 1.
26. Leber R., Silles E., Sandoval I.V., Mazon M.J. Yol082p, a novel CVT protein involved in the selective targeting of aminopeptidase I to the yeast vacuole. J Biol Chem. 276:2001;29210-29217. The authors show, by two-hybrid, that Cvt19 interacts with precursor Ape1 (prApe1), and to a lesser extent mature Ape1, and that Cvt19 is required for prApe1 targeting to the vacuole.
27. Hutchins M.U., Klionsky D.J. Vacuolar localization of oligomeric (mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J Biol Chem. 276:2001;20491-20498. This study provides compelling evidence that α-mannosidase, another resident vacuolar hydrolase, is targeted to the vacuole via the Cvt pathway, similar to prApe1.
28. Noda T., Kim J., Huang W.P., Baba M., Tokunaga C., Ohsumi Y., Klionsky D.J. Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J Cell Biol. 148:2000;465-480. This paper describes the cloning and characterization of APG9. The APG9 gene product is the first integral membrane protein required for Cvt vesicle and autophagosome formation. On the basis of these characteristics, the authors speculate that Apg9 is involved in marking the membrane site involved in initiating vesicle formation.
29. Lang T., Reiche S., Straub M., Bredschneider M., Thumm M. Autophagy and the Cvt pathway both depend on AUT9. J Bacteriol. 182:2000;2125-2133.
30. Wang C.W., Kim J., Huang W.P., Abeliovich H., Stromhaug P.E., Dunn W.A. Jr, Klionsky D.J. Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. J Biol Chem. 276:2001;30442-30451.
31. Shintani T., Suzuki K., Kamada Y., Noda T., Ohsumi Y. Apg2p functions in autophagosome formation on the perivacuolar structure. J Biol Chem. 276:2001;30452-30460.
32. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2:2001;211-216.
33. Mizushima N., Noda T., Yoshimori T., Tanaka Y., Ishii T., George M.D., Klionsky D.J., Ohsumi M., Ohsumi Y. A protein conjugation system essential for autophagy. Nature. 395:1998;395-398.
34. Tanida I., Mizushima N., Kiyooka M., Ohsumi M., Ueno T., Ohsumi Y., Kominami E. Apg7p/Cvt2p: a novel protein-activating enzyme essential for autophagy. Mol Biol Cell. 10:1999;1367-1379.
35. Kim J., Dalton V.M., Eggerton K.P., Scott S.V., Klionsky D.J. Apg7p/Cvt2p is required for the cytoplasm to vacuole targeting, macroautophagy, and peroxisome degradation pathways. Mol Biol Cell. 10:1999;1337-1351.
36. Shintani T., Mizushima N., Ogawa Y., Matsuura A., Noda T., Ohsumi Y. Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. EMBO J. 18:1999;5234-5241.
37. Mizushima N., Noda T., Ohsumi Y. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J. 18:1999;3888-3896.
38. George M.D., Baba M., Scott S.V., Mizushima N., Garrison B.S., Ohsumi Y., Klionsky D.J. Apg5p functions in the sequestration step in the cytoplasm to vacuole targeting and macroautophagy pathways. Mol Biol Cell. 11:2000;969-982. Previous studies (Mizushima et al. 1998 [33], Shintani et al. [1999] [36] and Mizushima et al. [1999] [37]) identified the Apg12-Apg5 ubiquitin-like conjugation system, including the coiled-coil Apg16 protein that crosslinks the conjugates. In this paper, the authors perform a detailed molecular study of a temperature-sensitive allele of APG5 and show that Apg5 is required to form completed autophagosomes. This work directly implicates the Apg12-Apg5 conjugation system in the process of vesicle formation.
39. Mizushima N., Sugita H., Yoshimori T., Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem. 273:1998;33889-33892.
40. Mizushima N., Yamamoto A., Hatano M., Kobayashi Y., Kabeya Y., Suzuki K., Tokuhisa T., Ohsumi Y., Yoshimori T. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 152:2001;657-668. Fluorescent-protein-tagged Apg5 is shown to localize to successive autophagosomal membrane intermediates in mouse embryonic stem cells. Paralleling yeast studies, conjugation of Apg12 to Apg5 is necessary for targeting one of the mouse homologues of Aut7 to membranes. Going beyond the yeast work, the conjugation is shown to play a role in elongation of early membrane precursors. This work augments previous morphological studies on autophagosome formation and identifies the potential structural role of Apg12-Apg5 conjugation in autophagosome formation in animal cells.
41. Ichimura Y., Kirisako T., Takao T., Satomi Y., Shimonishi Y., Ishihara N., Mizushima N., Tanida I., Kominami E., Ohsumi M., et al. A ubiquitin-like system mediates protein lipidation. Nature. 408:2000;488-492. The authors show that a novel ubiquitin-like conjugation system mediates the lipidation of Apg8/Aut7, resulting in covalent linkage of Aut7 to phosphatidylethanolamine.
42. Kirisako T., Ichimura Y., Okada H., Kabeya Y., Mizushima N., Yoshimori T., Ohsumi M., Takao T., Noda T., Ohsumi Y. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol. 151:2000;263-276. This paper details the molecular action of the cysteine protease Aut2/Apg4 and shows that Aut2 is required for Aut7 binding with, and dissociation from, membranes.
43. Kim J., Huang W.P., Klionsky D.J. Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and the autophagy conjugation complex. J Cell Biol. 152:2001;51-64. Investigators delineate molecular steps necessary for Aut7 membrane association. Factors involved are Aut1, Aut2 and the Apg12-Apg5 conjugate, all of which are required at the step of vesicle formation/completion in autophagy and the Cvt pathway.
44. Komatsu M., Tanida I., Ueno T., Ohsumi M., Ohsumi Y., Kominami E. The C-terminal region of an Apg7p/Cvt2p is required for homodimerization and is essential for its E1 activity and E1-E2 complex formation. J Biol Chem. 276:2001;9846-9854.
45. Kirisako T., Baba M., Ishihara N., Miyazawa K., Ohsumi M., Yoshimori T., Noda T., Ohsumi Y. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol. 147:1999;435-446.
46. Huang W.P., Scott S.V., Kim J., Klionsky D.J. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem. 275:2000;5845-5851. The authors show that Aut7/Apg8 expression is induced during autophagy and that Aut7 travels to the vacuole via Cvt vesicles and autophagosomes. Along with Kirisako et al. (1999) [45], this work provides evidence that Aut7 plays a direct structural role in the formation of autophagosomes.
47. Human Apg3p/Aut1p homologue is an E2 enzyme for multiple substrates, GATE-16. GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p
48. Darsow T., Rieder S.E., Emr S.D. A multispecificity syntaxin homologue, Vam3p, essential for autophagic and biosynthetic protein transport to the vacuole. J Cell Biol. 138:1997;517-529.
49. Sato T.K., Darsow T., Emr S.D. Vam7p, a SNAP-25-like molecule, and Vam3p, a syntaxin homolog, function together in yeast vacuolar protein trafficking. Mol Cell Biol. 18:1998;5308-5319.
50. Scott S.V., Baba M., Ohsumi Y., Klionsky D.J. Aminopeptidase I is targeted to the vacuole by a nonclassical vesicular mechanism. J Cell Biol. 138:1997;37-44.
51. Rieder S.E., Emr S.D. A novel RING finger protein complex essential for a late step in protein transport to the yeast vacuole. Mol Biol Cell. 8:1997;2307-2327.
52. Sato T.K., Rehling P., Peterson M.R., Emr S.D. Class C Vps protein complex regulates vacuolar SNARE pairing and is required for vesicle docking/fusion. Mol Cell. 6:2000;661-671.
53. Seals D.F., Eitzen G., Margolis N., Wickner W.T., Price A. A Ypt/Rab effector complex containing the Sec1 homolog Vps33p is required for homotypic vacuole fusion. Proc Natl Acad Sci USA. 97:2000;9402-9407.
54. Nakamura N., Matsuura A., Wada Y., Ohsumi Y. Acidification of vacuoles is required for autophagic degradation in the yeast Saccharomyces cerevisiae. J Biochem (Tokyo). 121:1997;338-344.
55. Takeshige K., Baba M., Tsuboi S., Noda T., Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 119:1992;301-311.
56. Suriapranata I., Epple U.D., Bernreuther D., Bredschneider M., Sovarasteanu K., Thumm M. The breakdown of autophagic vesicles inside the vacuole depends on Aut4p. J Cell Sci. 113:2000;4025-4033.
57. Teter S.A., Eggerton K.P., Scott S.V., Kim J., Fischer A.M., Klionsky D.J. Degradation of lipid vesicles in the yeast vacuole requires function of Cvt17, a putative lipase. J Biol Chem. 276:2001;2083-2087. Cvt17 is characterized as an integral membrane-glycosylated protein required to lyse autophagic and Cvt bodies in the vacuole. Cvt17 has a consensus sequence that is conserved among lipases. Mutational analysis demonstrated the importance of the putative active-site serine within the lipase domain.
58. Epple U.D., Suriapranata I., Eskelinen E.L., Thumm M. Aut5/Cvt17p a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J Bacteriol. 183:2001;5942-5955. The authors identify and characterize Cvt17 and show that it is transported via the multivesicular body pathway.
59. Veenhuis M., Douma A., Harder W., Osumi M. Degradation and turnover of peroxisomes in the yeast Hansenula polymorpha induced by selective inactivation of peroxisomal enzymes. Arch Microbiol. 134:1983;193-203.
60. Tuttle D.L., Lewin A.S., Dunn W.A. Jr. Selective autophagy of peroxisomes in methylotrophic yeasts. Eur J Cell Biol. 60:1993;283-290.
61. Tuttle D.L., Dunn W.A. Jr. Divergent modes of autophagy in the methylotrophic yeast Pichia pastoris. J Cell Sci. 108:1995;25-35.
62. Stromhaug P.E., Bevan A., Dunn W.A.J.r. GSA11 encodes a unique 208-kDa protein required for pexophagy and autophagy in Pichia pastoris. J Biol Chem. 276:2001;42422-42435. Researchers use a random mutagenesis approach to screen for glucose-induced selective autophagy of peroxisomes (GSA) mutants in P. Pastoris. One of the genes identified in the screen, GSA11, is characterized and shown to be a homologue of S. cerevisiae APG2. Gsa11 is required for pexophagy and autophagy.
63. Bellu A.R., Komori M., van der Klei I.J., Kiel J.A., Veenhuis M. Peroxisome biogenesis and selective degradation converge at Pex14p. J Biol Chem. 276:2001;44570-44574.
64. Stasyk O.V., van der Klei I.J., Bellu A.R., Shen S., Kiel J.A., Cregg J.M., Veenhuis M. A Pichia pastoris VPS15 homologue is required in selective peroxisome autophagy. Curr Genet. 36:1999;262-269.
65. Kiel J.A., Rechinger K.B., van der Klei I.J., Salomons F.A., Titorenko V.I., Veenhuis M. The Hansenula polymorpha PDD1 gene product, essential for the selective degradation of peroxisomes, is a homologue of Saccharomyces cerevisiae Vps34p. Yeast. 15:1999;741-754.
66. Yuan W., Stromhaug P.E., Dunn W.A.J.r. Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein. Mol Biol Cell. 10:1999;1353-1366.
67. Guan J., Stromhaug P.E., George M.D., Habibzadegah-Tari P., Bevan A., Dunn W.A. Jr, Klionsky D.J. Cvt18/Gsa12 is required for cytoplasm to vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. Mol Biol Cell. 12:2001;3821-3838.