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The biochemistry of apoptosis

Abstract

Apoptosis — the regulated destruction of a cell — is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

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References

  1. Vaux, D. L. & Korsmeyer, S. J. Cell death in development. Cell 96, 245–254 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wyllie, A. H., Kerr, J. F. & Currie, A. R. Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251–306 (1980).

    Article  CAS  PubMed  Google Scholar 

  4. Alnemri, E. S. et al. Human ICE/CED-3 protease nomenclature. Cell 87, 171 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Budihardjo, I., Oliver, H., Lutter, M., Luo, X. & Wang, X. Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol. 15, 269–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Cikala, M., Wilm, B., Hobmayer, E., Bottger, A. & David, C. N. Identification of caspases and apoptosis in the simple metazoan Hydra. Curr. Biol. 9, 959– 962 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Earnshaw, W. C., Martins, L. M. & Kaufmann, S. H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Thornberry, N. A. & Lazebnik, Y. Caspases: enemies within. Science 281, 1312– 1316 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Thornberry, N. A. et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J. Biol. Chem. 272, 17907–17911 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555– 556 (1980).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Nagata, S. Apoptotic DNA fragmentation. Exp. Cell Res. 256, 12–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Liu, X., Zou, H., Slaughter, C. & Wang, X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89, 175– 184 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43– 50 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Sakahira, H., Enari, M. & Nagata, S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391, 96– 99 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Rao, L., Perez, D. & White, E. Lamin proteolysis facilitates nuclear events during apoptosis . J. Cell Biol. 135, 1441– 1455 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Buendia, B., Santa-Maria, A. & Courvalin, J. C. Caspase-dependent proteolysis of integral and peripheral proteins of nuclear membranes and nuclear pore complex proteins during apoptosis . J. Cell Sci. 112, 1743– 1753 (1999).

    CAS  PubMed  Google Scholar 

  17. Kothakota, S. et al. Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278, 294– 298 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Rudel, T. & Bokoch, G. M. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science 276, 1571–1574 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  19. Nicholson, D. W. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028– 1042 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Muzio, M., Stockwell, B. R., Stennicke, H. R., Salvesen, G. S. & Dixit, V. M. An induced proximity model for caspase-8 activation. J. Biol. Chem. 273, 2926–2930 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Yang, X., Chang, H. Y. & Baltimore, D. Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Science 281, 1355– 1357 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Salvesen, G. S. & Dixit, V. M. Caspase activation: the induced-proximity model. Proc. Natl Acad. Sci. USA 96, 10964–10967 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rodriguez, J. & Lazebnik, Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 13, 3179– 3184 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stennicke, H. R. et al. Caspase-9 can be activated without proteolytic processing . J. Biol. Chem. 274, 8359– 8362 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Zou, H., Henzel, W. J., Liu, X., Lutschg, A. & Wang, X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90, 405–413 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  27. Beere, H. M. et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nature Cell Biol. 2, 469–475 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Cain, K. et al. Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1. 4-MDa apoptosome complexes. J. Biol. Chem. 275, 6067–6070 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  29. Cain, K., Brown, D. G., Langlais, C. & Cohen, G. M. Caspase activation involves the formation of the aposome, a large (approximately 700 kDa) caspase-activating complex. J. Biol. Chem. 274, 22686–22692 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Hofmann, K. The modular nature of apoptotic signaling proteins. Cell Mol. Life Sci. 55, 1113–1128 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  31. Huang, B., Eberstadt, M., Olejniczak, E. T., Meadows, R. P. & Fesik, S. W. NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384, 638–641 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  32. Eberstadt, M. et al. NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 392, 941– 945 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  33. Zhou, P., Chou, J., Olea, R. S., Yuan, J. & Wagner, G. Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: a structural basis for specific adaptor/caspase interaction . Proc. Natl Acad. Sci. USA 96, 11265– 11270 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reed, J. C. Double identity for proteins of the Bcl-2 family. Nature 387, 773–776 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322– 1326 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Antonsson, B. & Martinou, J. C. The Bcl-2 protein family. Exp. Cell Res. 256, 50–57 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Metzstein, M. M., Stanfield, G. M. & Horvitz, H. R. Genetics of programmed cell death in C. elegans : past, present and future. Trends Genet. 14, 410–416 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Pan, G., O'Rourke, K. & Dixit, V. M. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex . J. Biol. Chem. 273, 5841– 5845 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Hu, Y., Benedict, M. A., Wu, D., Inohara, N. & Nunez, G. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc. Natl Acad. Sci. USA 95, 4386–4391 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hausmann, G. et al. Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L). J. Cell Biol. 149, 623–634 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gross, A., McDonnell, J. M. & Korsmeyer, S. J. BCL-2 family members and the mitochondria in apoptosis . Genes Dev. 13, 1899–1911 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Muchmore, S. W. et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381, 335– 341 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Shimizu, S., Narita, M. & Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483–487 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  44. Loeffler, M. & Kroemer, G. The mitochondrion in cell death control: certainties and incognita. Exp. Cell Res. 256, 19–26 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Scaffidi, C. et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675–1687 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lorenzo, H. K., Susin, S. A., Penninger, J. & Kroemer, G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase- independent effector of cell death. Cell Death Differ. 6, 516–524 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).

    CAS  PubMed  Google Scholar 

  48. Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).

    CAS  PubMed  Google Scholar 

  49. Robertson, G. S., Crocker, S. J., Nicholson, D. W. & Schulz, J. B. Neuroprotection by the inhibition of apoptosis. Brain Pathol. 10, 283–292 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Nicholson, D. W. ICE/CED3-like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotechnol. 14, 297– 301 (1996).

    Article  CAS  Google Scholar 

  51. Zheng, T. S., Hunot, S., Kuida, K. & Flavell, R. A. Caspase knockouts: matters of life and death. Cell Death Differ. 6, 1043–1053 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, J. & Lenardo, M. J. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies . J. Cell Sci. 113, 753– 757 (2000).

    CAS  PubMed  Google Scholar 

  53. Miller, L. K. An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol. 9, 323–328 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Green, D. & Kroemer, G. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol. 8, 267–271 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Green, D. R. & Reed, J. C. Mitochondria and apoptosis. Science 281, 1309–1312 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  56. Abrams, J. M. An emerging blueprint for apoptosis in Drosophila. Trends Cell Biol. 9, 435–440 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  57. Borner, C. & Monney, L. Apoptosis without caspases: an inefficient molecular guillotine? Cell Death Differ. 6, 497–507 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Kitanaka, C. & Kuchino, Y. Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ. 6, 508–515 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Depraetere, V. & Golstein, P. Dismantling in cell death: molecular mechanisms and relationship to caspase activation. Scand. J. Immunol. 47, 523–531 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Irmler, M. et al. Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195 ( 1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  62. Gross, A. et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J. Biol. Chem. 274, 1156–1163 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis . Cell 94, 491–501 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Wolter, K. G. et al. Movement of Bax from the cytosol to mitochondria during apoptosis . J. Cell Biol. 139, 1281– 1292 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287– 296 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Jaattela, M. Escaping cell death: survival proteins in cancer. Exp. Cell Res. 248, 30–43 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  67. Xanthoudakis, S. & Nicholson, D. W. Heat shock proteins as death determinants. Nature Cell Biol. 2 , E163–E165 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886– 891 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  69. Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).

    Article  ADS  CAS  PubMed  Google Scholar 

  70. McDonnell, J. M., Fushman, D., Milliman, C. L., Korsmeyer, S. J. & Cowburn, D. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 96, 625–634 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  71. Chou, J. J., Li, H., Salvesen, G. S., Yuan, J. & Wagner, G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96, 615– 624 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Sattler, M. et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983 –986 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, H. et al. BAR: an apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. Proc. Natl Acad. Sci. USA 97 , 2597–2602 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ng, F. W. et al. p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum. J. Cell Biol. 139, 327–338 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chau, B. N., Cheng, E. H., Kerr, D. A. & Hardwick, J. M. Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Mol. Cell 6, 31–40 ( 2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

It is impossible to circumscribe the field of apoptosis in such a short review. I apologize to my many colleagues for having failed to cite their seminal papers and/or the critical results that clearly demonstrate their favourite model to be right. Many thanks to Y. Lazebnik for contributions to Box 3, and to Y.L., S. Lowe and members of the apoptosis community at Cold Spring Harbor Laboratory for many stimulating discussions. I dedicate this review to W. Hengartner on the occasion of his retirement from active mathematical duty.

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Hengartner, M. The biochemistry of apoptosis. Nature 407, 770–776 (2000). https://doi.org/10.1038/35037710

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