Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Canonical and non-canonical autophagy: variations on a common theme of self-eating?

Nature Reviews Molecular Cell Biology volume 13, pages 7–12 (2012)Cite this article

Subjects

Abstract

The autophagosome is the central organelle in macroautophagy, a vacuolar lysosomal catabolic pathway that degrades cytoplasmic material to fuel starving cells and eliminates intracellular pathogens. Macroautophagy has important physiological roles during development, ageing and the immune response, and its cytoprotective function is compromised in various diseases. A set of autophagy-related (ATG) proteins is hierarchically recruited to the phagophore, the initial membrane template in the construction of the autophagosome. However, recent findings suggest that macroautophagy can also occur in the absence of some of these key autophagy proteins, through the unconventional biogenesis of canonical autophagosomes. Such alternatives to the evolutionarily conserved scheme might provide additional therapeutic opportunities.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathways of canonical and non-canonical autophagy.
Figure 2: Examples of non-canonical autophagy structures.

Similar content being viewed by others

References

  1. Yang, Z. & Klionsky, D. J. Eaten alive: a history of macroautophagy. Nature Cell Biol. 12, 814–822 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hailey, D. W. et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656–667 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C. & Rubinsztein, D. C. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nature Cell Biol. 12, 747–757 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Young, A. R. et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119, 3888–3900 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Proikas-Cezanne, T. et al. WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23, 9314–9325 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Mauthe, M. et al. Resveratrol-mediated autophagy requires WIPI-1 regulated LC3 lipidation in the absence of induced phagophore formation. Autophagy 7, 1448–1461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Polson, H. E. et al. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6, 506–522 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Proikas-Cezanne, T. & Robenek, H. Freeze-fracture replica immunolabelling reveals human WIPI-1 and WIPI-2 as membrane proteins of autophagosomes. J. Cell. Mol. Med. 15, 2007–2010 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ferguson, C. J., Lenk, G. M. & Meisler, M. H. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum. Mol. Genet. 18, 4868–4878 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Proikas-Cezanne, T., Ruckerbauer, S., Stierhof, Y. D., Berg, C. & Nordheim, A. Human WIPI-1 puncta-formation: a novel assay to assess mammalian autophagy. FEBS Lett. 581, 3396–3404 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Meijer, A. J. & Codogno, P. Autophagy: regulation by energy sensing. Curr. Biol. 21, R227–R229 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Mari, M. et al. An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J. Cell Biol. 190, 1005–1022 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nair, U. et al. SNARE proteins are required for macroautophagy. Cell 146, 290–302 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moreau, K., Ravikumar, B., Renna, M., Puri, C. & Rubinsztein, D. C. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303–317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weidberg, H. et al. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev. Cell 20, 444–454 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Nakatogawa, H., Ichimura, Y. & Ohsumi, Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130, 165–178 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Funderburk, S. F., Wang, Q. J. & Yue, Z. The Beclin 1-VPS34 complex-at the crossroads of autophagy and beyond. Trends Cell Biol. 20, 355–362 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. He, C. & Levine, B. The Beclin 1 interactome. Curr. Opin. Cell Biol. 22, 140–149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Proikas-Cezanne, T. & Codogno, P. Beclin 1 or not Beclin 1. Autophagy 7, 671–672 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Zhu, J. H. et al. Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am. J. Pathol. 170, 75–86 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Scarlatti, F., Maffei, R., Beau, I., Codogno, P. & Ghidoni, R. Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 15, 1318–1329 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Tian, S. et al. Beclin 1-independent autophagy induced by a Bcl-XL/Bcl-2 targeting compound, Z18. Autophagy 6, 1032–1041 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Grishchuk, Y., Ginet, V., Truttmann, A. C., Clarke, P. G. & Puyal, J. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 7, 1115–1131 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Arsov, I. et al. A role for autophagic protein beclin 1 early in lymphocyte development. J. Immunol. 186, 2201–2209 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Mestre, M. B., Fader, C. M., Sola, C. & Colombo, M. I. α-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus-infected cells. Autophagy 6, 110–125 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Smith, D. M. et al. Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells. Cell Death Differ. 17, 1867–1881 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Gao, P. et al. The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J. Biol. Chem. 285, 25570–25581 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheong, H., Lindsten, T., Wu, J., Lu, C. & Thompson, C. B. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc. Natl Acad. Sci. USA 108, 11121–11126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grotemeier, A. et al. AMPK-independent induction of autophagy by cytosolic Ca2+ increase. Cell. Signal. 22, 914–925 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Yamamoto, A., Cremona, M. L. & Rothman, J. E. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Mortensen, M. et al. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc. Natl Acad. Sci. USA 107, 832–837 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, J. et al. Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation. Blood 114, 157–164 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505–516 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Itoh, T., Kanno, E., Uemura, T., Waguri, S. & Fukuda, M. OATL1, a novel autophagosome-resident Rab33B-GAP, regulates autophagosomal maturation. J. Cell Biol. 192, 839–853 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Yamaguchi, H. et al. An initial step of GAS-containing autophagosome-like vacuoles formation requires Rab7. PLoS Pathog. 5, e1000670 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gutierrez, M. G., Munafo, D. B., Beron, W. & Colombo, M. I. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J. Cell Sci. 117, 2687–2697 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Jager, S. et al. Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117, 4837–4848 (2004).

    Article  PubMed  Google Scholar 

  44. Shui, W. et al. Membrane proteomics of phagosomes suggests a connection to autophagy. Proc. Natl Acad. Sci. USA 105, 16952–16957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nature Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  Google Scholar 

  46. Virgin, H. W. & Levine, B. Autophagy genes in immunity. Nature Immunol. 10, 461–470 (2009).

    Article  CAS  Google Scholar 

  47. Andrade, R. M., Wessendarp, M., Gubbels, M. J., Striepen, B. & Subauste, C. S. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116, 2366–2377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sanjuan, M. A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253–1257 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Martinez, J. et al. Microtubule-associated protein 1 light chain 3 α (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl Acad. Sci. USA 108, 17396–17401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Amer, A. O. & Swanson, M. S. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell. Microbiol. 7, 765–778 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Florey, O., Kim, S. E., Sandoval, C. P., Haynes, C. M. & Overholtzer, M. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nature Cell Biol. 13, 1335–1343 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).

    Article  CAS  Google Scholar 

  56. Weidberg, H., Shvets, E. & Elazar, Z. Biogenesis and cargo selectivity of autophagosomes. Annu. Rev. Biochem. 80, 125–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Orenstein, S. J. & Cuervo, A. M. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin. Cell Dev. Biol. 21, 719–726 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Noda, T. & Farquhar, M. G. A non-autophagic pathway for diversion of ER secretory proteins to lysosomes. J. Cell Biol. 119, 85–97 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. Klionsky, D. J. et al. A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy 7, 1273–1294 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories was supported by institutional grants from INSERM (Institut National de la Santé et de la Recherche Médicale), Université Paris-Sud 11, the ANR (Agence Nationale de la Recherche) and INCa (Institut National du Cancer) to P.C. and M.M.; and from the German Research Society (DFG, SFB 773) to T.P.-C.

Author information

Authors and Affiliations

  1. Patrice Codogno and Maryam Mehrpour are at the Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris-Sud 11, 92296 Châtenay-Malabry, France.,

    Patrice Codogno & Maryam Mehrpour

  2. Tassula Proikas-Cezanne is at the Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.,

    Tassula Proikas-Cezanne

Authors
  1. Patrice Codogno
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Maryam Mehrpour
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Tassula Proikas-Cezanne
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Patrice Codogno.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Tassula Proikas-Cezanne's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Codogno, P., Mehrpour, M. & Proikas-Cezanne, T. Canonical and non-canonical autophagy: variations on a common theme of self-eating?. Nat Rev Mol Cell Biol 13, 7–12 (2012). https://doi.org/10.1038/nrm3249

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3249

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing