Skip to main content

Advertisement

SpringerLink
Log in

Microautophagy: lesser-known self-eating

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Microautophagy, the non-selective lysosomal degradative process, involves direct engulfment of cytoplasmic cargo at a boundary membrane by autophagic tubes, which mediate both invagination and vesicle scission into the lumen. With its constitutive characteristics, microautophagy of soluble substrates can be induced by nitrogen starvation or rapamycin via regulatory signaling complex pathways. The maintenance of organellar size, membrane homeostasis, and cell survival under nitrogen restriction are the main functions of microautophagy. In addition, microautophagy is coordinated with and complements macroautophagy, chaperone-mediated autophagy, and other self-eating pathways. Three forms of selective microautophagy, including micropexophagy, piecemeal microautophagy of the nucleus, and micromitophagy, share common ground with microautophagy to some degree. As the accumulation of experimental data, the precise mechanisms that govern microautophagy are becoming more appreciated. Here, we review the microautophagic molecular machinery, its physiological functions, and relevance to human diseases, especially in diseases involving multivesicular bodies and multivesicular lysosomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

Alp:

Alkaline phosphatase

Apg/Atg/ATG/Aut :

Autophagy-related gene

CMA:

Chaperone-mediated autophagy

Cpy:

Carboxypeptidase Y

CVT:

Cytoplasm-to-vacuole targeting

EGO:

Exit from rapamycin-induced growth arrest

ESCRT:

Endosomal sorting complex required for transport

hsc70:

Heat shock cognate 70

MIPA:

Micropexophagic membrane apparatus

MPT:

Mitochondrial permeability transition

MVB:

Multivesicular body

NV:

Nucleus–vacuole

PAS:

Pre-autophagosomal structure

PCD:

Programmed cell death

PE:

Phosphatidylethanolamine

PMN:

Piecemeal microautophagy of the nucleus

PVS:

Peri-vacuolar dot-like structures

ROS:

Reactive oxygen species

SNARE:

Soluble NSF attachment protein receptors

TOR:

Target of rapamycin

Ublc:

Ubiquitin-like conjugation

VSM:

Vacuolar sequestering membrane

VTC:

Vacuolar transporter chaperone

References

  1. deDuve C (1963) The lysosome. Sci Am 208:64–72

    Article  CAS  Google Scholar 

  2. Klionsky DJ (2008) Autophagy revisited: a conversation with Christian de Duve. Autophagy 4:740–743

    PubMed  Google Scholar 

  3. Cecconi F, Levine B (2008) The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell 15:344–357

    Article  PubMed  CAS  Google Scholar 

  4. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B (2010) Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy 6:322–329

    Article  PubMed  CAS  Google Scholar 

  5. Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Bio 9:1004–1010

    Article  CAS  Google Scholar 

  6. deDuve C, Wattiaux R (1966) Functions of lysosomes. Annu Rev Physiol 28:435–492

    Article  CAS  Google Scholar 

  7. Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18

    Article  PubMed  CAS  Google Scholar 

  8. Neff NT, Bourret L, Miao P, Dice JF (1981) Degradation of proteins microinjected into IMR-90 human diploid fibroblasts. J Cell Biol 91:184–194

    Article  PubMed  CAS  Google Scholar 

  9. Ahlberg J, Marzella L, Glaumann H (1982) Uptake and degradation of proteins by isolated rat liver lysosomes. Suggestion of a microautophagic pathway of proteolysis. Lab Invest 47:523–532

    PubMed  CAS  Google Scholar 

  10. Mortimore GE, Lardeux BR, Adams CE (1988) Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation. J Biol Chem 263:2506–2512

    PubMed  CAS  Google Scholar 

  11. Kunz JB, Schwarz H, Mayer A (2004) Determination of four sequential stages during microautophagy in vitro. J Biol Chem 279:9987–9996

    Article  PubMed  CAS  Google Scholar 

  12. Bellu AR, Kram AM, Kiel JA, Veenhuis M, van der Klei IJ (2001) Glucose-induced and nitrogen-starvation-induced peroxisome degradation are distinct processes in Hansenula polymorpha that involve both common and unique genes. FEMS Yeast Res 1:23–31

    PubMed  CAS  Google Scholar 

  13. Bolender RP, Weibel ER (1973) A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of treatment. J Cell Biol 56:746–761

    Article  PubMed  CAS  Google Scholar 

  14. Klöppel G, Ruttmann E, Bommer G, Schäfer HJ (1976) Crinophagy and insulin secretion B cell morphology after various inhibition of insulin secretion. Verh Dtsch Ges Pathol 220–224

  15. Smith JD, de Harven E (1978) Herpes simplex virus and human cytomegalovirus replication in WI-38 cells. III. Cytochemical localization of lysosomal enzymes in infected cells. J Virol 26:102–109

    PubMed  CAS  Google Scholar 

  16. Bormann C, Sahm H (1978) Degradation of microbodies in relation to activities of alcohol oxidase and catalase in Candida boidinii. Arch Microbiol 117:67–72

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. Chiang HL, Schekman R (1991) Regulated import and degradation of a cytosolic protein in the yeast vacuole. Nature 350:313–318

    Article  PubMed  CAS  Google Scholar 

  19. Harding TM, Morano KA, Scott SV, Klionsky DJ (1995) Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol 131:591–602

    Article  PubMed  CAS  Google Scholar 

  20. Xue L, Fletcher GC, Tolkovsky AM (2001) Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr Biol 11:361–365

    Article  PubMed  CAS  Google Scholar 

  21. Roberts P, Moshitch-Moshkovitz S, Kvam E, O’Toole E, Winey M, Goldfarb DS (2003) Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell 14:129–141

    Article  PubMed  CAS  Google Scholar 

  22. Kissova I, Deffieu M, Manon S, Camougrand N (2004) Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem 279:39068–39074

    Article  PubMed  CAS  Google Scholar 

  23. Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, Kopito RR (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci USA 102:13135–13140

    Article  PubMed  CAS  Google Scholar 

  24. Uttenweiler A, Mayer A (2008) Microautophagy in the yeast Saccharomyces cerevisiae. Methods Mol Biol 445:245–259

    Article  PubMed  CAS  Google Scholar 

  25. Tian Y, Li Z, Hu W, Ren H, Tian E, Zhao Y, Lu Q, Huang X, Yang P, Li X, Wang X, Kovács AL, Yu L, Zhang H (2010) C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141:1042–1055

    Article  PubMed  CAS  Google Scholar 

  26. Uttenweiler A, Schwarz H, Mayer A (2005) Microautophagic vacuole invagination requires calmodulin in a Ca2+ independent function. J Biol Chem 280:33289–33297

    Article  PubMed  CAS  Google Scholar 

  27. Müller O, Sattler T, Flötenmeyer M, Schwarz H, Plattner H, Mayer A (2000) Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J Cell Biol 151:519–528

    Article  PubMed  Google Scholar 

  28. Sattler T, Mayer A (2000) Cell-free reconstitution of microautophagic vacuole invagination and vesicle formation. J Cell Biol 151:529–538

    Article  PubMed  CAS  Google Scholar 

  29. Doelling JH, Walker JM, Friedman EM, Thompson AR, Vierstra RD (2002) The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J Biol Chem 277:33105–33114

    Article  PubMed  CAS  Google Scholar 

  30. Sou YS, Waguri S, Iwata J, Ueno T, Fujimura T, Hara T, Sawada N, Yamada A, Mizushima N, Uchiyama Y, Kominami E, Tanaka K, Komatsu M (2008) The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol Biol Cell 19:4762–4775

    Article  PubMed  CAS  Google Scholar 

  31. Ichimura Y et al (2000) A ubiquitin-like system mediates protein lipidation. Nature 408:488–492

    Article  PubMed  CAS  Google Scholar 

  32. Uttenweiler A, Schwarz H, Neumann H, Mayer A (2007) The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol Biol Cell 18:166–175

    Article  PubMed  CAS  Google Scholar 

  33. Noda T, Suzuki T, Ohsumi Y (2002) Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol 12:231–235

    Article  PubMed  CAS  Google Scholar 

  34. Müller O, Neumann H, Bayer MJ, Mayer A (2003) Role of the Vtc proteins in V-ATPase stability and membrane trafficking. J Cell Sci 116:1107–1115

    Article  PubMed  Google Scholar 

  35. Bayer MJ, Reese C, Buhler S, Peters C, Mayer A (2003) Vacuole membrane fusion: V0 functions after trans-SNARE pairing and is coupled to the Ca2+-releasing channel. J Cell Biol 162:211–222

    Article  PubMed  CAS  Google Scholar 

  36. Epple UD, Suriapranata I, Eskelinen EL, Thumm M (2001) Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J Bacteriol 183:5942–5955

    Article  PubMed  CAS  Google Scholar 

  37. Yang Z, Klionsky DJ (2007) Permeases recycle amino acids resulting from autophagy. Autophagy 3:149–150

    PubMed  CAS  Google Scholar 

  38. Liu B, Cheng Y, Liu Q, Bao JK, Yang JM (2010) Autophagic pathways as new targets for cancer drug development. Acta Pharmacol Sin 31:1154–1164

    Article  PubMed  CAS  Google Scholar 

  39. Jacinto E, Hall MN (2003) TOR signalling in bugs, brain and brawn. Nat Rev Mol Cell Bio 4:117–126

    Article  CAS  Google Scholar 

  40. Crespo JL, Powers T, Fowler B, Hall MN (2002) The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine. Proc Natl Acad Sci USA 99:6784–6789

    Article  PubMed  CAS  Google Scholar 

  41. Butow RA, Avadhani NG (2004) Mitochondrial signaling: the retrograde response. Mol Cell 14:1–15

    Article  PubMed  CAS  Google Scholar 

  42. Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y (2010) TOR directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 30:1049–1058

    Article  PubMed  CAS  Google Scholar 

  43. Cherkasova VA, Hinnebusc AG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2α kinase GCN2. Genes Dev 17:859–872

    Article  PubMed  CAS  Google Scholar 

  44. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477

    Article  PubMed  CAS  Google Scholar 

  45. Ashrafi K, Farazi TA, Gordon JI (1998) A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N-myristoylation during entry into stationary phase. J Biol Chem 273:25864–25874

    Article  PubMed  CAS  Google Scholar 

  46. Zhu H, Bilgin M, Bangham R, Hall D, Casamayor A, Bertone P, Lan N, Jansen R, Bidlingmaier S, Houfek T et al (2001) Global analysis of protein activities using proteome chips. Science 293:2101–2105

    Article  PubMed  CAS  Google Scholar 

  47. Dubouloz F, Deloche O, Wanke V, Cameroni E, De Virgilio C (2005) The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol Cell 19:15–26

    Article  PubMed  CAS  Google Scholar 

  48. Sakai Y, Koller A, Rangell LK, Keller GA, Subramani S (1998) Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological intermediates. J Cell Biol 141:625–636

    Article  PubMed  CAS  Google Scholar 

  49. Farré JC, Krick R, Subramani S, Thumm M (2009) Turnover of organelles by autophagy in yeast. Curr Opin Cell Biol 21:522–530

    Article  PubMed  Google Scholar 

  50. Farré JC, Subramani S (2004) Peroxisome turnover by micropexophagy: an autophagy-related process. Trends Cell Biol 14:515–523

    Article  PubMed  Google Scholar 

  51. Veenhuis M, Salomons FA, Van Der Klei IJ (2000) Peroxisome biogenesis and degradation in yeast: a structure/function analysis. Microsc Res Tech 51:584–600

    Article  PubMed  CAS  Google Scholar 

  52. Dawaliby R, Mayer A (2010) Microautophagy of the nucleus coincides with a vacuolar diffusion barrier at nuclear-vacuolar junctions. Mol Biol Cell 21:4173–4183

    Article  PubMed  CAS  Google Scholar 

  53. Krick R, Mühe Y, Prick T, Bredschneider M, Bremer S, Wenzel D, Eskelinen EL, Thumm M (2009) Piecemeal microautophagy of the nucleus: genetic and morphological traits. Autophagy 5:270–272

    Article  PubMed  CAS  Google Scholar 

  54. Krick R, Muehe Y, Prick T, Bremer S, Schlotterhose P, Eskelinen E-L, Millen J, Goldfarb DS, Thumm M (2008) Piecemeal microautophagy of the nucleus requires the core macroautophagy genes. Mol Biol Cell 19:4492–4505

    Article  PubMed  CAS  Google Scholar 

  55. Millen JI, Krick R, Prick T, Thumm M, Goldfarb DS (2009) Measuring piecemeal microautophagy of the nucleus in Saccharomyces cerevisiae. Autophagy 5:75–81

    Article  PubMed  CAS  Google Scholar 

  56. Kvam E, Gable K, Dunn TM, Goldfarb DS (2005) Targeting of Tsc13p to nucleus–vacuole junctions: a role for very-long chain fatty acids in the biogenesis of microautophagic vesicles. Mol Cell Biol 16:3987–3998

    Article  CAS  Google Scholar 

  57. Kissová I, Salin B, Schaeffer J, Bhatia S, Manon S, Camougrand N (2007) Selective and non-selective autophagic degradation of mitochondria in yeast. Autophagy 3:329–336

    PubMed  Google Scholar 

  58. Kraft C, Reggiori F, Peter M (2009) Selective types of autophagy in yeast. Biochim Biophys Acta 1793:1404–1412

    Article  PubMed  CAS  Google Scholar 

  59. Deffieu M, Bhatia-Kissová I, Salin B, Galinier A, Manon S, Camougrand N (2009) Glutathione participates in the regulation of mitophagy in yeast. J Biol Chem 284:14828–14837

    Article  PubMed  CAS  Google Scholar 

  60. Cuervo MA (2004) Autophagy: many paths to the same end. Mol Cell Biochem 263:55–72

    Article  PubMed  CAS  Google Scholar 

  61. Monastryska I, Sjollema K, van der Klei IJ, Kiel JA, Veenhuis M (2004) Microautophagy and macropexophagy may occur simultaneously in Hansenula polymorpha. FEBS Lett 568:135–138

    Article  PubMed  CAS  Google Scholar 

  62. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77

    Article  PubMed  Google Scholar 

  63. Todde V, Veenhuis M, van der Klei IJ (2009) Autophagy: principles and significance in health and disease. Biochim Biophys Acta 1792:3–13

    PubMed  CAS  Google Scholar 

  64. Saksena S, Emr SD (2009) ESCRTs and human disease. Biochem Soc Trans 37:167–172

    Article  PubMed  CAS  Google Scholar 

  65. Takikita S, Myerowitz R, Zaal K, Raben N, Plotz PH (2009) Murine muscle cell models for Pompe disease and their use in studying therapeutic approaches. Mol Genet Metab 96:208–217

    Article  PubMed  CAS  Google Scholar 

  66. Katzmann DJ, Odorizzi G, Emr SD (2002) Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3:893–905

    Article  PubMed  CAS  Google Scholar 

  67. Lata S, Schoehn G, Solomons J, Pires R, Göttlinger HG, Weissenhorn W (2009) Structure and function of ESCRT-III. Biochem Soc Trans 37:156–160

    Article  PubMed  CAS  Google Scholar 

  68. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20:405–406

    Article  CAS  Google Scholar 

  69. Kumari S, Mg S, Mayor S (2010) Endocytosis unplugged: multiple ways to enter the cell. Cell Res 20:256–275

    Article  PubMed  CAS  Google Scholar 

  70. Shpilka T, Elazar Z (2011) Shedding light on mammalian microautophagy. Dev Cell 20:1–2

    Article  PubMed  CAS  Google Scholar 

  71. Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091

    Article  PubMed  CAS  Google Scholar 

  72. Boellaard JW, Schlote W, Tateishi J (1989) Neuronal autophagy in experimental Creutzfeldt-Jakob’s disease. Acta Neuropathol 78:410–418

    Article  PubMed  CAS  Google Scholar 

  73. Liberski PP, Sikorska B, Budka H (2006) Enlarged multivesicular bodies in Gerstmann-Straussler-Scheinker disease suggest the involvement of microautophagy in prion disease. Alzheimers Dement 2:S560–S561

    Article  Google Scholar 

  74. Martín-Aparicio E, Yamamoto A, Hernández F, Hen R, Avila J, Lucas JJ (2001) Proteasomal dependent aggregate reversal and absence of cell death in a condition of mouse model of Huntington’s disease. J Neurosci 21:8772–8781

    PubMed  Google Scholar 

  75. Ray K, Chaki M, Sengupta M (2007) Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. Prog Retin Eye Res 26:323–358

    Article  PubMed  CAS  Google Scholar 

  76. Sen T, Mullerpattan J, Agarwal D, Naphde D, Deshpande R, Mahashur AA (2009) Hermansky-Pudlak syndrome. J Assoc Physicians India 57:660–662

    PubMed  Google Scholar 

  77. Zhang H, Mahuran DJ, Callahan JW (2010) Identification of proteins in the ceroid-like autofluorescent aggregates from liver lysosomes of Beige, a mouse model for human Chediak-Higashi syndrome. Mol Genet Metab 99:389–395

    Article  PubMed  CAS  Google Scholar 

  78. Takikita S, Myerowitz R, Schreiner C, Baum R, Raben N, Plotz PH (2009) The values and limits of an in vitro model of Pompe disease: the best laid schemes o’ mice an’ men. Autophagy 5:729–731

    Article  PubMed  CAS  Google Scholar 

  79. de Waal EJ, Vreeling-Sindelárová H, Schellens JP, James J (1986) Starvation-induced microautophagic vacuoles in rat myocardial cells. Cell Biol Int Rep 10:527–533

    Article  PubMed  Google Scholar 

  80. Morse D, Lin L, Choi AM, Ryter SW (2009) Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease. Free Radic Biol Med 47:1–12

    Article  PubMed  CAS  Google Scholar 

  81. Klionsky DJ, Cuervo AM, Dunn WA Jr, Levine B, van der Klei I, Seglen PO (2007) How shall I eat thee? Autophagy 3:413–416

    PubMed  Google Scholar 

  82. 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Bo Liu for providing constructive suggestions, Yi Wang, Zi-yue Li, Jun-jie Liu and Qian Liu for critically reading the manuscript, and Chi Yang, Hao-yu Hu for technical assistance. This work was supported in part by grants from the National Natural Science Foundation of China (No. 30970643, No. 81173093 and No. J1103518), and National Key Technologies R&D Program of 11th 5-year plan.

Author information

Authors and Affiliations

  1. School of Life Sciences and State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, 610064, China

    Wen-wen Li & Jin-ku Bao

  2. Molecular and Cellular Biology Program, Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA

    Jian Li

Authors
  1. Wen-wen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-ku Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-ku Bao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Ww., Li, J. & Bao, Jk. Microautophagy: lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125–1136 (2012). https://doi.org/10.1007/s00018-011-0865-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0865-5

Keywords

Search

Navigation