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The origin of the autophagosomal membrane

Abstract

Macroautophagy is initiated by the formation of the phagophore (also called the isolation membrane). This membrane can both selectively and non-selectively engulf cytosolic components, grow and close around the sequestered components and then deliver them to a degradative organelle, the lysosome. Where this membrane comes from and how it grows is not well understood. Since the discovery of autophagy in the 1950s the source of the membrane has been investigated, debated and re-investigated, with the consensus view oscillating between a de novo assembly mechanism or formation from the membranes of the endoplasmic reticulum (ER) or the Golgi. In recent months, new information has emerged that both the ER and mitochondria may provide a membrane source, enlightening some older findings and revealing how complex the initiation of autophagy may be in mammalian cells.

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Figure 1: Potential sources for the phagophore include the Golgi complex, endosomes, ER and mitochondria.
Figure 2: Model for recruitment of Atg proteins and DFCP1 to the ER-derived membrane and formation of the phagophore.

References

  1. 1

    Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Hayashi-Nishino, M. et al. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11, 1433–1437 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Yla-Anttila, P., Vihinen, H., Jokitalo, E. & Eskelinen, E. L. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180–1185 (2009).

    Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Novikoff, P. M., Novikoff, A. B., Quintana, N. & Hauw, J. J. Golgi apparatus, GERL and lysosomes of neurons in rat dorsal root ganglia, studied by thick section and thin section cytochemistry. J. Cell Biol. 50, 859–886 (1971).

    CAS  Article  Google Scholar 

  6. 6

    Reunanen, H., Punnonen, E. L. & Hirsimäki, P. Studies on vinblastine-induced autophagocytosis in mouse liver. V. A cytochemical study on the origin of membranes. Histochemistry 83, 513–517 (1985).

    CAS  Article  Google Scholar 

  7. 7

    Fengsrud, M., Erichsen, E. S., Berg, T. O., Raiborg, C. & Seglen, P. O. Ultrastructural characterization of the delimiting membranes of isolated autophagosomes and amphisomes by freeze-fracture electron microscopy. Eur. J. Cell Biol. 79, 871–882 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Rez, G. & Meldolesi, J. Freeze-fracture of drug-induced autophagocytosis in the mouse exocrine pancreas. Lab. Invest. 43, 269–277 (1980).

    CAS  PubMed  Google Scholar 

  9. 9

    Punnonen, E. L., Pihakaski, K., Mattila, K., Lounatmaa, K. & Hirsimaki, P. Intramembrane particles and filipin labelling on the membranes of autophagic vacuoles and lysosomes in mouse liver. Cell Tissue Res. 258, 269–276 (1989).

    CAS  Article  Google Scholar 

  10. 10

    Hirsimaki, Y., Hirsimaki, P. & Lounatmaa, K. Vinblastine-induced autophagic vacuoles in mouse liver and Ehrlich ascites tumor cells as assessed by freeze-fracture electron microscopy. Eur. J. Cell Biol. 27, 298–301 (1982).

    CAS  PubMed  Google Scholar 

  11. 11

    Stromhaug, P. E., Berg, T. O., Fengsrud, M. & Seglen, P. O. Purification and characterization of autophagosomes from rat hepatocytes. Biochem. J. 335, 217–224 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Orsi, A., Polson, H. E. & Tooze, S. A. Membrane trafficking events that partake in autophagy. Curr. Opin. Cell Biol. 22, 150–156 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Thumm, M. et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 349, 275–280 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Mari, M. et al. Key role of a novel Atg9-containing compartment in the early steps of autophagosome biogenesis. J. Cell Biol. doi:10.1080/jcb200912089 (2010).

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Webber, J. L. & Tooze, S. A. New insights into the function of Atg9. FEBS Lett. 584, 1319–1326 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl Acad. Sci. USA 106, 20842–20846 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Yen, W. L. et al. The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J. Cell Biol. 188, 101–114 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Geng, J., Nair, U., Yasumura-Yorimitsu, K. & Klionsky, D. J. Post-Golgi sec proteins are required for autophagy in Saccharomyces cerevisiae. Mol. Biol. Cell 21, 2257–2269 (2010).

    CAS  Article  Google Scholar 

  24. 24

    van der Vaart, A., Griffith, J. & Reggiori, F. Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol. Biol. Cell 21, 2270–2284 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Lynch-Day, M. A. et al. Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. Proc. Natl Acad. Sci. USA 107, 7811–7816 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Chan, E. Y. W. & Tooze, S. A. Evolution and expansion of Atg1 function. Autophagy 5, 758–765 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Simonsen, A. & Tooze, S. A. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J. Cell Biol. 186, 773–782 (2009).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    Matsunaga, K. et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat. Cell Biol. 11, 385–396 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Matsunga, K. et al. Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J. Cell Biol. doi: 10.1083/jcb.200911141 (2010).

  31. 31

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

    CAS  Article  Google Scholar 

  32. 32

    Proikas-Cezanne, T. et al. WIPI-1 (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 58, 9314–9325 (2004).

    Article  Google Scholar 

  33. 33

    Fujita, N. et al. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol. Biol. Cell 19, 4651–4659 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Kornmann, B. et al. An ER–mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009).

    CAS  Article  Google Scholar 

  35. 35

    Hamasaki, M. & Yoshimori, T. Where do they come from? Insights into autophagosome formation. FEBS Lett. 584, 1296–1301 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Reggiori, F. & Tooze, S. A. The emergence of autophagosomes. Dev. Cell 17, 747–748 (2009).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

S.A.T. would like to thank Cancer Research U.K. for funding. T. Y. was supported by Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Takeda Science Foundation.

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Tooze, S., Yoshimori, T. The origin of the autophagosomal membrane. Nat Cell Biol 12, 831–835 (2010). https://doi.org/10.1038/ncb0910-831

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