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Autophagy: dual roles in life and death?

Abstract

Autophagy is an evolutionarily conserved mechanism for the degradation of cellular components in the cytoplasm, and serves as a cell survival mechanism in starving cells. Recent studies indicate that autophagy also functions in cell death, but the precise role of this catabolic process in dying cells is not clear. Here I discuss the possible roles for autophagy in dying cells and how understanding the relationship between autophagy, cell survival and cell death is important for health and development.

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Figure 1: Genetic regulation of autophagy.
Figure 2: Cell death can involve both caspases and autophagy.
Figure 3: Possible roles of autophagy in cell survival and death.

References

  1. 1

    Conlon, I. & Raff, M. Size control in animal development. Cell 96, 235–244 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Baehrecke, E. H. How death shapes life during development. Nature Rev. Mol. Cell Biol. 3, 779–787 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Schweichel, J. U. & Merker, H. J. The morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266 (1973).

    CAS  Article  Google Scholar 

  6. 6

    Clarke, P. G. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181, 195–213 (1990).

    CAS  Article  Google Scholar 

  7. 7

    Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    CAS  Article  Google Scholar 

  8. 8

    Leist, M. & Jäätelä, M. Four deaths and a funeral: from caspases to alternative mechanisms. Nature Rev. Mol. Cell Biol. 2, 589–598 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717–1721 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Reggiori, F. & Klionsky, D. J. Autophagy in the eukaryotic cell. Eukaryot. Cell 1, 11–21 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Ohsumi, Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nature Rev. Mol. Cell Biol. 2, 211–216 (2001).

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

    Harding, T. M., Morano, K. A., Scott, S. V. & Klionsky, D. J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).

    CAS  Article  Google Scholar 

  19. 19

    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, 992–998 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Scott, R. C., Schuldiner, O. & Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Arico, S. et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276, 35243–35246 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Rusten, T. E. et al. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev. Cell 7, 179–192 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Kamada, Y. et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507–1513 (2000).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Suzuki, K. et al. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20, 5971–5981 (2001).

    CAS  Article  Google Scholar 

  27. 27

    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, 763–773 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    CAS  Article  Google Scholar 

  29. 29

    Ogier-Denis, E. & Codogno, P. Autophagy: a barrier or an adaptive response to cancer. Biochim. Biophys. Acta 1603, 113–128 (2003).

    CAS  PubMed  Google Scholar 

  30. 30

    Franke, T. F., Hornik, C. P., Segev, L., Shostak, G. A. & Sugimoto, C. PI3K/Akt and apoptosis: size matters. Oncogene 22, 8983–8998 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Datta, S. R. et al. Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev. Cell 3, 631–643 (2002).

    CAS  Article  Google Scholar 

  32. 32

    Jaattela, M. & Tschopp, J. Caspase-independent cell death in T lymphocytes. Nature Immunol. 4, 416–423 (2003).

    Article  Google Scholar 

  33. 33

    Shi, Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell 9, 459–470 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Kawahara, A., Ohsawa, Y., Matsumura, H., Uchiyama, Y. & Nagata, S. Caspase-independent cell killing by Fas-associated protein with death domain. J. Cell Biol. 143, 1353–1360 (1998).

    CAS  Article  Google Scholar 

  35. 35

    Vercammen, D. et al. Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 188, 919–930 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunol. 1, 489–495 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Matsumura, H. et al. Necrotic death pathway in Fas receptor signaling. J. Cell Biol. 151, 1247–1256 (2000).

    CAS  Article  Google Scholar 

  38. 38

    Lee, C. Y. & Baehrecke, E. H. Steroid regulation of autophagic programmed cell death during development. Development 128, 1443–1455 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Martin, D. N. & Baehrecke, E. H. Caspases function in autophagic cell death in Drosophila. Development 131, 275–284 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Lee, C. Y., Cooksey, B. A. & Baehrecke, E. H. Steroid regulation of midgut cell death during Drosophila development. Dev. Biol. 250, 101–111 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Debnath, J. et al. The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell 111, 29–40 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Mills, K. R., Reginato, M., Debnath, J., Queenan, B. & Brugge, J. S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl Acad. Sci. USA 101, 3438–3443 (2004).

    CAS  Article  Google Scholar 

  43. 43

    Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25, 1025–1040 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Lee, C. Y. et al. Genome-wide analyses of steroid- and radiation-triggered programmed cell death in Drosophila. Curr. Biol. 13, 350–357 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Jesenberger, V. & Jentsch, S. Deadly encounter: ubiquitin meets apoptosis. Nature Rev. Mol. Cell Biol. 3, 112–121 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Onodera, J. & Ohsumi, Y. Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae. J. Biol. Chem. 279, 16071–16076 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Inbal, B., Bialik, S., Sabanay, I., Shani, G. & Kimchi, A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J. Cell Biol. 157, 455–468 (2002).

    CAS  Article  Google Scholar 

  48. 48

    Nakano, Y. et al. Mutations in the novel membrane protein spinster interfere with programmed cell death and cause neural degeneration in Drosophila melanogaster. Mol. Cell Biol. 21, 3775–3788 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Yanagisawa, H., Miyashita, T., Nakano, Y. & Yamamoto, D. HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-xL, induces a caspase-independent autophagic cell death. Cell Death Differ. 10, 798–807 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998).

    CAS  Article  Google Scholar 

  51. 51

    Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    CAS  Article  Google Scholar 

  52. 52

    Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).

    CAS  Article  Google Scholar 

  53. 53

    Yoshida, H. et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739–750 (1998).

    CAS  Article  Google Scholar 

  54. 54

    Chautan, M., Chazal, G., Cecconi, F., Gruss, P. & Golstein, P. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol. 9, 967–970 (1999).

    CAS  Article  Google Scholar 

  55. 55

    Oppenheim, R. W. et al. Programmed cell death of developing mammalian neurons after genetic deletion of caspases. J. Neurosci. 21, 4752–4760 (2001).

    CAS  Article  Google Scholar 

  56. 56

    Shintani, T. & Klionsky, D. J. Autophagy in health and disease: a double-edged sword. Science 306, 990–995 (2004).

    CAS  Article  Google Scholar 

  57. 57

    Alva, A. S., Gultekin, S. H. & Baehrecke, E. H. Autophagy in human tumors: cell survival or death? Cell Death Differ. 11, 1046–1048 (2004).

    CAS  Article  Google Scholar 

  58. 58

    Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    CAS  Article  Google Scholar 

  59. 59

    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 

  60. 60

    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 

  61. 61

    Liang, X. H. et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72, 8586–8596 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    CAS  Article  Google Scholar 

  63. 63

    Arama, E., Agapite, J. & Steller, H. Caspase activity and a specific cytochrome c are required for sperm differentiation in Drosophila. Dev. Cell 4, 687–697 (2003).

    CAS  Article  Google Scholar 

  64. 64

    Huh, J. R. et al. Multiple apoptotic caspase cascades are required in nonapoptotic roles for Drosophila spermatid individualization. PLoS Biol. 2, E15 (2004).

    Article  Google Scholar 

  65. 65

    Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002).

    CAS  Article  Google Scholar 

  66. 66

    Klionsky, D. J. Regulated self-cannibalism. Nature 431, 31–32 (2004).

    CAS  Article  Google Scholar 

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Acknowledgements

I apologize to many researchers who were not referenced owing to space limitations. I thank D. Berry, L. Yu, and M. Lenardo for discussions and comments on this manuscript. Studies of autophagy and cell death in my laboratory are supported by the National Institutes of Health.

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DATABASES

Swiss-Prot

Akt

Atg3

Atg4

Atg5

Atg7

Atg8

Atg10

Atg12

Atg16

PI3K

PTEN

TSC1

TSC2

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Baehrecke, E. Autophagy: dual roles in life and death?. Nat Rev Mol Cell Biol 6, 505–510 (2005). https://doi.org/10.1038/nrm1666

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