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  • Review Article
  • Published:

Expansion and evolution of cell death programmes

Nature Reviews Molecular Cell Biology volume 9, pages 378–390 (2008)Cite this article

Key Points

  • Mammalian apoptosis originates from the apoptosis machinery of primitive organisms, such as the nematode C. elegans.

  • Evolution of apoptosis has led to the expansion of the protein families of apoptosis regulators. The driving forces for this process can probably be traced to the needs of complex multicellular organisms to increase the fidelity of apoptosis execution (redundancy of apoptosis regulation) and the efficiency of the apoptosis signalling pathways, fitted to respond to the distinct extracellular and intracellular stimuli.

  • Similarity of mammalian CED-4-like molecules to both C.elegans apoptotic CED-4 protein and to the NLR proteins that are involved in the innate immune response of primitive organisms suggest that the mammalian apoptotic machinery might have originated from the convergence of these two pathways, driven by the need for better defences from pathogen invasion.

  • Multiple pathways of non-apoptotic cell death have recently been described, namely autophagic cell death, necroptosis and poly (ADP–ribose) polymerase-1 (PARP1)-mediated cell death. Emerging data provided the first insights into the cellular regulation of these processes.

  • Emerging data also suggest that non-apoptotic cell death pathways might have evolved to play important physiological parts in cellular responses to stress, genotoxic damage and pathogenic infection.

  • The emerging complex interplay of apoptotic and non-apoptotic cell death mechanisms in animal models of human pathologies suggests that development of the approaches to inhibit apoptosis and, in many cases, non-apoptotic cell death, might be key to the development of successful cytoprotective therapies.

Abstract

Cell death has historically been subdivided into regulated and unregulated mechanisms. Apoptosis, a form of regulated cell death, reflects a cell's decision to die in response to cues and is executed by intrinsic cellular machinery. Unregulated cell death (often called necrosis) is caused by overwhelming stress that is incompatible with cell survival. Emerging evidence, however, suggests that these two processes do not adequately explain the various cell death mechanisms. Recent data point to the existence of multiple non-apoptotic, regulated cell death mechanisms, some of which overlap or are mutually exclusive with apoptosis. Here we examine how and why these different cell death programmes have evolved, with an eye towards new cytoprotective therapeutic opportunities.

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Figure 1: Evolutionary expansion of C. elegans apoptotic machinery in mammalian cells.
Figure 2: Mammalian NLR proteins and NB-LRR proteins from simpler organisms have similar functions.
Figure 3: Plasticity of cell death activation in vivo.
Figure 4: Activation of alternative cell fates following TNFα stimulation.

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References

  1. Yuan, J. & Horvitz, H. R. A first insight into the molecular mechanisms of apoptosis. Cell 116, S53–S56 (2004). The authors provide in-depth insight into the discovery of the apoptotic machinery in C. elegans .

    Article  CAS  PubMed  Google Scholar 

  2. Clarke, P. G. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181, 195–213 (1990). This paper provides an early morphological analysis of developmental cell death and describes the existence of multiple forms of PCD.

    Article  CAS  Google Scholar 

  3. Twomey, C. & McCarthy, J. V. Pathways of apoptosis and importance in development. J. Cell. Mol. Med. 9, 345–359 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Wei, M. C. et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McConkey, D. J. Biochemical determinants of apoptosis and necrosis. Toxicol. Lett. 99, 157–168 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Zong, W. X. & Thompson, C. B. Necrotic death as a cell fate. Genes Dev. 20, 1–15 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Horvitz, H. R., Shaham, S. & Hengartner, M. O. The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harb. Symp. Quant. Biol. 59, 377–385 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Conradt, B. & Xue, D. Programmed cell death. WormBook, 1–13 (2005).

  11. 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 

  12. Hofmann, E. R. et al. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr. Biol. 12, 1908–1918 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Tait, S. W. et al. Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment. J. Cell Biol. 179, 1453–1466 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Konishi, Y., Lehtinen, M., Donovan, N. & Bonni, A. Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol. Cell 9, 1005–1016 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Zha, J., Weiler, S., Oh, K. J., Wei, M. C. & Korsmeyer, S. J. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290, 1761–1765 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol. 9, 47–59 (2008).

    Article  CAS  Google Scholar 

  18. Scorrano, L. & Korsmeyer, S. J. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304, 437–444 (2003). This paper describes in detail the molecular mechanism of the key step in apoptosis where mitochondrial cytochrome c is released.

    Article  CAS  PubMed  Google Scholar 

  19. Willis, S. N. et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315, 856–859 (2007). This paper presents evidence that suggests that anti-apoptotic BCL2 family members, rather than BAX and BAK, are the targets of BH3-only proteins.

    Article  CAS  PubMed  Google Scholar 

  20. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim. Biophys. Acta 1757, 639–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Degterev, A., Boyce, M. & Yuan, J. A decade of caspases. Oncogene 22, 8543–8567 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Schulze-Osthoff, K., Ferrari, D., Los, M., Wesselborg, S. & Peter, M. E. Apoptosis signaling by death receptors. Eur. J. Biochem. 254, 439–459 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003). In this paper, upstream signalling events that lead to the activation of apoptosis are described.

    Article  CAS  PubMed  Google Scholar 

  24. Barnhart, B. C., Alappat, E. C. & Peter, M. E. The CD95 type I/type II model. Semin. Immunol. 15, 185–193 (2003). In this paper, distinct pathways (direct or mitochondria-mediated) of executioner caspase activation by death receptors are described in detail.

    Article  CAS  PubMed  Google Scholar 

  25. McStay, G. P., Salvesen, G. S. & Green, D. R. Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways. Cell Death Differ. 15, 322–331 (2007).

    Google Scholar 

  26. Sprick, M. R. et al. Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. EMBO J. 21, 4520–4530 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Su, H. et al. Requirement for caspase-8 in NF-kB activation by antigen receptor. Science 307, 1465–1468 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Lassus, P., Opitz-Araya, X. & Lazebnik, Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297, 1352–1354 (2002). In this paper, a specific role for caspase-2 in genotoxic stress-induced apoptosis is shown.

    Article  CAS  PubMed  Google Scholar 

  29. Hitomi, J. et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J. Cell Biol. 165, 347–356 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98–103 (2000). This paper provides the first demonstration of the specific role of caspase-12 in ER stress response.

    Article  CAS  PubMed  Google Scholar 

  31. Zou, H., Li, Y., Liu, X. & Wang, X. An APAF-1cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 274, 11549–11556 (1999). The authors establish the existence of the caspase-9-activating apoptotosome complex.

    Article  CAS  PubMed  Google Scholar 

  32. Gao, Z., Shao, Y. & Jiang, X. Essential roles of the Bcl-2 family of proteins in caspase-2-induced apoptosis. J. Biol. Chem. 280, 38271–38275 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999). This is one of the earliest papers establishing specific roles of a particular BH3-only factor, BIM, in response to specific upstream signals.

    Article  CAS  PubMed  Google Scholar 

  34. Yu, J. & Zhang, L. The transcriptional targets of p53 in apoptosis control. Biochem. Biophys. Res. Commun. 331, 851–588 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Schmelzle, T. et al. Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc. Natl Acad. Sci. USA 104, 3787–3792 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen, L. et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 (2005). This paper demonstrates that selective interactions of pro- and anti-apoptotic BCL2 family members contribute to the regulation of the mitochondrial step in apoptosis.

    Article  CAS  PubMed  Google Scholar 

  37. Takai, Y. et al. Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells. Apoptosis 12, 791–800 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Troy, C. M. et al. Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J. Neurosci. 21, 5007–5016 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Garcia-Calvo, M. et al. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 273, 32608–32613 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Abraham, M. C., Lu, Y. & Shaham, S. A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. Dev. Cell 12, 73–86 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yuan, J. Inducing autophagy harmlessly. Autophagy 4, 249–250 (2007).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007). This paper demonstrates that autophagic cell death is specifically activated during development under apoptosis-competent conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Marino, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573–18583 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004). This paper demonstrates the crucial role of autophagy in vivo in maintaining survival under nutrient-deprivation conditions.

    Article  CAS  PubMed  Google Scholar 

  48. Juhasz, G., Erdi, B., Sass, M. & Neufeld, T. P. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev. 21, 3061–3066 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Espert, L. et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J. Clin. Invest. 116, 2161–2172 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pattingre, S., Espert, L., Biard-Piechaczyk, M. & Codogno, P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90, 313–323 (2007).

    Article  PubMed  CAS  Google Scholar 

  51. Maiuri, M. C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev. Mol. Cell Biol. 8, 741–752 (2007).

    Article  CAS  Google Scholar 

  52. Ullman, E. et al. Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ. 15, 422–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. Oberstein, A., Jeffrey, P. D. & Shi, Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J. Biol. Chem. 282, 13123–13132 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005). This paper presents evidence for the regulation of autophagy by the anti-apoptotic BCL2 family members, establishing convergent regulation of apoptosis and autophagy.

    Article  CAS  PubMed  Google Scholar 

  56. Tracy, K. & Macleod, K. F. Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy 3, 616–619 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Rashmi, R., Pillai, S. G., Vijayalingam, S., Ryerse, J. & Chinnadurai, G. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27, 1366–1375 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Khwaja, A. & Tatton, L. Resistance to the cytotoxic effects of tumor necrosis factor α can be overcome by inhibition of a FADD/caspase-dependent signaling pathway. J. Biol. Chem. 274, 36817–36823 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chan, F. K. et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 278, 51613–51621 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chem. Biol. 1, 112–119 (2005). This paper describes a first-in-class potent and selective inhibitor of necroptosis.

    Article  CAS  Google Scholar 

  64. 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). In this paper, the crucial role of RIP1 kinase activity in the activation of necroptosis is first demonstrated.

    Article  CAS  Google Scholar 

  65. 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). This paper is one of the initial reports showing induction of necrotic death by death-domain receptor signals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Festjens, N., Vanden Berghe, T. & Vandenabeele, P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim. Biophys. Acta 1757, 1371–1387 (2006). This paper provides an in-depth analysis of the signalling and execution pathways of regulated necrosis.

    Article  CAS  PubMed  Google Scholar 

  67. Zheng, L. et al. Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol. Cell Biol. 26, 3505–3513 (2006). This paper shows that apoptotic and necroptotic signalling pathways diverge at the level of the death-domain receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, K. et al. Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5. Bioorg. Med. Chem. Lett. 17, 1455–1465 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Jagtap, P. G. et al. Structure-activity relationship study of tricyclic necroptosis inhibitors. J. Med. Chem. 50, 1886–1895 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Teng, X. et al. Structure-activity relationship study of novel necroptosis inhibitors. Bioorg. Med. Chem. Lett. 15, 5039–5044 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Temkin, V., Huang, Q., Liu, H., Osada, H. & Pope, R. M. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol. Cell Biol. 26, 2215–2225 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lim, S. Y., Davidson, S. M., Mocanu, M. M., Yellon, D. M. & Smith, C. C. The cardioprotective effect of necrostatin requires the cyclophilin-D component of the mitochondrial permeability transition pore. Cardiovasc. Drugs Ther. 21, 467–469 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Suzuki, S. et al. Nur77 as a survival factor in tumor necrosis factor signaling. Proc. Natl Acad. Sci. USA 100, 8276–8280 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jagtap, P. & Szabo, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nature Rev. Drug Discov. 4, 421–440 (2005).

    Article  CAS  Google Scholar 

  75. Oei, S. L., Keil, C. & Ziegler, M. Poly(ADP-ribosylation) and genomic stability. Biochem. Cell Biol. 83, 263–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q. & Thompson, C. B. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272–1282 (2004). This paper establishes the existence of the 'death by energy collapse' mechanism of PARP-1-mediated cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ditsworth, D., Zong, W. X. & Thompson, C. B. Activation of poly(ADP)-ribose polymerase (PARP-1) induces release of the pro-inflammatory mediator HMGB1 from the nucleus. J. Biol. Chem. 282, 17845–17854 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Andrabi, S. A. et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc. Natl Acad. Sci. USA 103, 18308–18313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yu, S. W. et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc. Natl Acad. Sci. USA 103, 18314–18319 (2006). This paper describes the mechanism of the PARP1–AIF cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Xu, Y., Huang, S., Liu, Z. G. & Han, J. Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J. Biol. Chem. 281, 8788–8795 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).

    Article  CAS  PubMed  Google Scholar 

  82. Aballay, A. & Ausubel, F. M. Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing. Proc. Natl Acad. Sci. USA 98, 2735–2739 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Martinon, F., Gaide, O., Petrilli, V., Mayor, A. & Tschopp, J. NALP inflammasomes: a central role in innate immunity. Semin. Immunopathol. 29, 213–229 (2007). This paper provides an extensive review of the mechanism of action and regulation of mammalian inflammasomes.

    Article  CAS  PubMed  Google Scholar 

  84. Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Ting, J. P., Kastner, D. L. & Hoffman, H. M. CATERPILLERs, pyrin and hereditary immunological disorders. Nature Rev. Immunol. 6, 183–195 (2006).

    Article  CAS  Google Scholar 

  86. Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002). This paper provides an initial report demonstrating the existance of the caspase-1 activating inflammasome complex.

    Article  CAS  PubMed  Google Scholar 

  88. Bruey, J. M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007). This paper presents evidence that inflammasome activity is inhibited by BCL2 family members.

    Article  CAS  PubMed  Google Scholar 

  89. Petrilli, V., Dostert, C., Muruve, D. A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Jones, J. D. & Dangl, J. L. The plant immune system. Nature 444, 323–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Faustin, B. et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 25, 713–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006).

    Article  CAS  Google Scholar 

  94. Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006). References 93 and 94 establish that IPAF inflammasomes can sense intracellular PAMP signals.

    Article  CAS  Google Scholar 

  95. Shen, Q. H. et al. Nuclear activity of MLA immune receptors links isolate-specific and basal disease-resistance responses. Science 315, 1098–1103 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Woltering, E. J. Death proteases come alive. Trends Plant Sci. 9, 469–472 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Vercammen, D., Declercq, W., Vandenabeele, P. & Van Breusegem, F. Are metacaspases caspases? J. Cell Biol. 179, 375–380 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schmid, D. & Munz, C. Innate and adaptive immunity through autophagy. Immunity 27, 11–21 (2007). Reference 98 provides a detailed overview of the role of autophagy in the immune regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004). This paper presents evidence that the activation of autophagy can serve a host defence function.

    Article  CAS  PubMed  Google Scholar 

  101. Py, B. F., Lipinski, M. M. & Yuan, J. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3, 117–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. 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 

  103. Xu, Y. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135–144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Meylan, E. & Tschopp, J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem. Sci. 30, 151–159 (2005). A detailed review that discusses the structure and function of the RIP kinase family.

    Article  CAS  PubMed  Google Scholar 

  106. Cusson-Hermance, N., Khurana, S., Lee, T. H., Fitzgerald, K. A. & Kelliher, M. A. Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation. J. Biol. Chem. 280, 36560–36566 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nature Immunol. 5, 503–507 (2004).

    Article  CAS  Google Scholar 

  108. Balachandran, S., Thomas, E. & Barber, G. N. A FADD-dependent innate immune mechanism in mammalian cells. Nature 432, 401–405 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Georgel, P. et al. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vanden Berghe, T. et al. Necrosis is associated with IL-6 production but apoptosis is not. Cell Signal 18, 328–335 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Korkina, O. & Degterev, A. in Wiley Encyclopedia of Chemical Biology (ed. Begley, T. P.) (John Wiley and Sons, Ltd, 2008).

    Google Scholar 

  113. Shimizu, S., Konishi, A., Kodama, T. & Tsujimoto, Y. BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc. Natl Acad. Sci. USA 97, 3100–3105 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cheng, E. H. et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278, 1966–1968 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Acehan, D. et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell 9, 423–432 (2002). This is the first paper to provide structural insight into the functioning of the apoptosome.

    Article  CAS  PubMed  Google Scholar 

  116. Park, H. H. et al. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128, 533–546 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007). This is an in-depth review that describes recent progress in understanding autophagic regulation.

    Article  CAS  PubMed  Google Scholar 

  118. Yu, L. et al. Regulation of an ATG7–beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004). This paper demonstrates activation of autophagic cell death resulting from caspase inhibition.

    Article  CAS  PubMed  Google Scholar 

  119. Kim, Y. S., Morgan, M. J., Choksi, S. & Liu, Z. G. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol. Cell 26, 675–687 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Schulze-Osthoff, K. et al. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J. Biol. Chem. 267, 5317–5323 (1992).

    Article  CAS  PubMed  Google Scholar 

  121. Festjens, N. et al. Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death Differ. 13, 166–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Thon, L. et al. Ceramide mediates caspase-independent programmed cell death. FASEB. J. 19, 1945–1956 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Ame, J. C., Spenlehauer, C. & de Murcia, G. The PARP superfamily. Bioessays 26, 882–893 (2004). This is a detailed review of the structure and function of PARP family members.

    Article  CAS  PubMed  Google Scholar 

  124. Vahsen, N. et al. AIF deficiency compromises oxidative phosphorylation. EMBO J. 23, 4679–4689 (2004). In this report, the metabolic function of AIF in the regulating activity of mitochondrial complex I is established.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhu, H. et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J. Clin. Invest. 117, 1782–1793 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Matsui, Y. et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100, 914–922 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007). This paper demonstrates that the induction of autophagy in cancer cells in vivo enhances tumour growth through the inhibition of apoptosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Edinger, A. L. & Thompson, C. B. Defective autophagy leads to cancer. Cancer Cell 4, 422–424 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006). This paper demonstrates the plasticity of cancer cell death activation under hypoxic conditions by demonstrating the activation of apoptosis, autophagy and necrosis that is dependent on the expression of specific protein factors in the cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Smith, C. C. et al. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc. Drugs Ther. 21, 227–233 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. de la Lastra, C. A., Villegas, I. & Sanchez-Fidalgo, S. Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr. Pharm. Des. 13, 933–962 (2007).

    Article  PubMed  Google Scholar 

  132. Horvath, E. M. & Szabo, C. Poly(ADP-ribose) polymerase as a drug target for cardiovascular disease and cancer: an update. Drug News Perspect. 20, 171–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Kauppinen, T. M. & Swanson, R. A. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145, 1267–1272 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Zaremba, T. & Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med. Chem. 7, 515–523 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Martinon, F. & Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14, 10–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Muppidi, J. R., Tschopp, J. & Siegel, R. M. Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21, 461–465 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C. & Ting, A. T. Ubiquitination of RIP1 regulates an NF-κB-independent cell-death switch in TNF signaling. Curr. Biol. 17, 418–424 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Hong, Q. et al. Zfra affects TNF-mediated cell death by interacting with death domain protein TRADD and negatively regulates the activation of NF-κB, JNK1, p53 and WOX1 during stress response. BMC Mol. Biol. 8, 50 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Takahashi, R. et al. Focal adhesion kinase determines the fate of death or survival of cells in response to TNFα in the presence of actinomycin D. Biochim. Biophys. Acta 1770, 518–526 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Leist, M. et al. Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp. Cell Res. 249, 396–403 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Leist, M., Single, B., Castoldi, A. F., Kuhnle, S. & Nicotera, P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185, 1481–1486 (1997). This paper introduces the idea that intrinsic differences in cellular energy levels might have a key role in the selection of a cell's form of death: either apoptotic or necrotic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Volbracht, C., Leist, M. & Nicotera, P. ATP controls neuronal apoptosis triggered by microtubule breakdown or potassium deprivation. Mol. Med. 5, 477–489 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nicotera, P., Leist, M., Fava, E., Berliocchi, L. & Volbracht, C. Energy requirement for caspase activation and neuronal cell death. Brain Pathol. 10, 276–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Dimmeler, S., Haendeler, J., Sause, A. & Zeiher, A. M. Nitric oxide inhibits APO-1/Fas-mediated cell death. Cell Growth Differ. 9, 415–422 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

J.Y. is supported in part by grants from the National Institute on Aging (NIA) Merit Award (R37 AG12859) and the National Institutes of Health (NIH) Director's Pioneer Award. A.D. is supported in part by NIA Mentored Research Scientist Career Development Award and Massachusetts Medical Foundation Smith Family New Investigator Award.

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Authors and Affiliations

  1. Department of Biochemistry, Tufts University, School of Medicine, 136 Harrison Ave., Boston, 02111, Massachusetts, USA

    Alexei Degterev

  2. Department of Cell Biology, Harvard Medical School, 200 Longwood Ave., Boston, 02115, Massachusetts, USA

    Junying Yuan

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  1. Alexei Degterev
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Correspondence to Junying Yuan.

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DATABASES

InterPro

LRRs

NACHT

Pyrin

UniProtKB

caspase-9

APAF1

BAX

BAK

EGL-1

CED-9

CED-4

CED-3

BCL2

BCL-XL

MCL1

FASL

TNFα

BID

BIM

PARP1

ATG5

ATG7

Beclin-1

CXCR4

RIP1

ANT

HMGB1

AIF

TRAF2

MAPK8

NAIP

NLRX1

NLRC4

CIITA

ASC

NALP1

PIDD

DAP

FURTHER INFORMATION

Junying Yuan's homepage

Alexei Degterev's homepage

Glossary

BH3-only member

Pro-apoptotic BCL2 family member possessing only a BCL2 homology-3 (BH3) domain.

Anoikis

Cell death caused by cell detachment from the matrix.

Linker cell

A cell in a C.elegans embryo that is positioned between the gonad and the cloacal tube.

Type I cell death

A term introduced as part of a morphological classification of developmental cell death. Type I death shows the morphological features of apoptosis.

ROS

(Reactive oxygen species). Highly reactive intermediates in the reduction of oxygen to water. These are produced, for example, as a byproduct of oxidative phosporylation in the mitochondria.

Type II cell death

A term introduced as part of a morphological classification of developmental cell death. Type II death shows the morphological features of autophagy.

Necroptosis

A process of regulated non-apoptotic cell death displaying necrotic morphology, which can be induced by death domain receptors through RIP1 kinase activity.

CD4+ T cell

One of a subpopulation of mature T cells that express the CD4 receptor.

NF-κB

(Nuclear factor-κB). A family of transcription factors that are activated by many inflammatory signals.

Cyclophilin D

A mitochondrial matrix protein that is associated with the mitochondria permeability pore.

NLR

A mammalian protein that is characterized by the presence of NACHT and Leu-rich repeat (LRR) domains.

PAMPs

Components of pathogens that are recognized by the innate immune system, including lipopolysaccharide, peptidoglycans and viral RNA.

DAMPS

Changes in the cellular environment that are associated with pathogenic infection, such as an increase in ATP concentration.

PIDDosome

A caspase-2-activating complex that is formed by the multimerization of PIDD and RAIDD proteins.

Macroautophagy

The sequestration of cytosolic components in autophagosomes and their subsequent degradation when autophagosomes fuse with lysosomes.

Interferon

An inflammatory cytokine that is produced by cells as part of the innate immune response.

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Degterev, A., Yuan, J. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 9, 378–390 (2008). https://doi.org/10.1038/nrm2393

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