Live to die another way: modes of programmed cell death and the signals emanating from dying cells

Key Points

  • During development, programmed cell death has various functions, including sculpting and deletion of structures, supply of nutrients, regulation of cell number and elimination of abnormal and dangerous cells.

  • Several distinct mechanisms of programmed cell death are used to eliminate cells; we discuss the biological significance of these pathways in vivo.

  • Caspase activation is subjected to many layers of coordinated upstream regulation, which ensure that the cell is killed only after several checkpoints have been cleared.

  • Is autophagy a cell death mechanism? Here, we carefully review the data that support autophagy as a bona fide mechanism of cell destruction.

  • For many years, necrosis was regarded as an unregulated mode of cell death that was caused by overwhelming trauma. Here, we examine a regulated form of necrosis termed necroptosis.

  • Traditionally, it was thought that dying cells have limited effects on the cellular environment. However, it is now clear that apoptotic cells release signals that can trigger tissue regeneration.

  • Cells that are undergoing apoptosis can instruct additional killing in their cellular environment, which explains how 'communal suicide' can occur.

Abstract

All life ends in death, but perhaps one of life's grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was almost synonymous with apoptosis; recently, however, alternative mechanisms of PCD have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals that emanate from dying cells, which can either trigger regeneration or instruct additional killing. Further advances in understanding the physiological roles of the various mechanisms of cell death and their associated signals will be important to selectively manipulate PCD for therapeutic purposes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The core of the apoptotic machinery is conserved.
Figure 2: Crosstalk between autophagy-related and apoptosis-related proteins.
Figure 3: Tumour necrosis factor-mediated survival, apoptosis and necroptosis.
Figure 4: Apoptosis-induced proliferation.
Figure 5: Apoptosis-induced apoptosis.

References

  1. 1

    Vogt, C. I. Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkröte (Alytes obstetricans) (in German) (Jent, 1842).

    Google Scholar 

  2. 2

    Lockshin, R. A. & Williams, C. M. Programmed cell death — II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J. Insect Physiol. 10, 643–649 (1964).

    CAS  Google Scholar 

  3. 3

    Tata, J. R. Requirement for RNA and protein synthesis for induced regression of the tadpole tail in organ culture. Dev. Biol. 13, 77–94 (1966).

    CAS  PubMed  Google Scholar 

  4. 4

    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  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    CAS  PubMed  Google Scholar 

  6. 6

    Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 ß-converting enzyme. Cell 75, 641–652 (1993). This is the first report of a cellular 'built-in' suicide mechanism.

    CAS  Google Scholar 

  7. 7

    Abraham, M. C. & Shaham, S. Death without caspases, caspases without death. Trends Cell Biol. 14, 184–193 (2004).

    CAS  PubMed  Google Scholar 

  8. 8

    Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011). This is a comprehensive review that examines the role of apoptosis in development and the non-apoptotic function of caspases.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Yi, C. H. & Yuan, J. The Jekyll and Hyde functions of caspases. Dev. Cell 16, 21–34 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    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).

    CAS  Google Scholar 

  11. 11

    Yuan, J. & Kroemer, G. Alternative cell death mechanisms in development and beyond. Genes Dev. 24, 2592–2602 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    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). This comprehensive review discusses the intricate relationship between apoptosis and autophagy.

    CAS  Google Scholar 

  13. 13

    Galluzzi, L. & Kroemer, G. Necroptosis: a specialized pathway of programmed necrosis. Cell 135, 1161–1163 (2008).

    CAS  PubMed  Google Scholar 

  14. 14

    Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature Rev. Mol. Cell Biol. 11, 700–714 (2010). This review provides a comprehensive analysis of the molecular mechanisms of necroptosis and the implications for human pathology.

    CAS  Google Scholar 

  15. 15

    Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. & Vandenabeele, P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nature Rev. Mol. Cell Biol. 15, 135–147 (2014).

    CAS  Google Scholar 

  16. 16

    Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347–354 (1997). This landmark review focuses on the function of apoptosis in animal development.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).

    CAS  PubMed  Google Scholar 

  18. 18

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

    CAS  PubMed  Google Scholar 

  19. 19

    Feinstein-Rotkopf, Y. & Arama, E. Can't live without them, can live with them: roles of caspases during vital cellular processes. Apoptosis 14, 980–995 (2009).

    PubMed  Google Scholar 

  20. 20

    Rodriguez, J. & Lazebnik, Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 13, 3179–3184 (1999). This elegant work shows that caspase 9 and APAF1 form an active holoenzyme in which caspase 9 is the catalytic subunit and APAF1 is its allosteric regulator.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Srivastava, M. et al. ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its apoptotic activity. Cell Death Differ. 14, 92–102 (2007).

    CAS  PubMed  Google Scholar 

  22. 22

    Nagasaka, A., Kawane, K., Yoshida, H. & Nagata, S. Apaf-1-independent programmed cell death in mouse development. Cell Death Differ. 17, 931–941 (2010). This report indicates that, in addition to the APAF1-dependent mechanism of apoptosis, APAF1-independent death systems exist.

    CAS  PubMed  Google Scholar 

  23. 23

    Xu, D., Li, Y., Arcaro, M., Lackey, M. & Bergmann, A. The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila. Development 132, 2125–2134 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006). This is an elegant study indicating that caspase 3 and caspase 7 can regulate a perceived upstream mitochondrial event of apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Edison, N. et al. The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo. Cell Death Differ. 19, 356–368 (2012). This report shows that ARTS regulates caspase activation upstream of MOMP.

    CAS  PubMed  Google Scholar 

  26. 26

    Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998). This is an elegant study elucidating CAD and its inhibitor, which regulate DNA degradation during apoptosis.

    CAS  PubMed  Google Scholar 

  27. 27

    Crook, N. E., Clem, R. J. & Miller, L. K. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J. Virol. 67, 2168–2174 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nature Rev. Mol. Cell Biol. 6, 287–297 (2005).

    CAS  Google Scholar 

  29. 29

    Wang, S. L., Hawkins, C. J., Yoo, S. J., Müller, H. A. & Hay, B. A. The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98, 453–463 (1999). This is a demonstration that Diap1 is inhibited by Hid and is required to block apoptosis-induced caspase activity.

    CAS  PubMed  Google Scholar 

  30. 30

    Goyal, L., McCall, K., Agapite, J., Hartwieg, E. & Steller, H. Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J. 19, 589–597 (2000). This in vivo study shows that RHG proteins kill as part of a complex with Diap1.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lisi, S., Mazzon, I. & White, K. Diverse domains of THREAD/DIAP1 are required to inhibit apoptosis induced by REAPER and HID in Drosophila. Genetics 154, 669–678 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Schile, A. J., Garcia-Fernandez, M. & Steller, H. Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes Dev. 22, 2256–2266 (2008). This is a demonstration of a physiological requirement for XIAP ubiquitin ligase activity for the inhibition of caspases and for tumour suppression in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M. & Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288, 874–877 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Ryoo, H. D., Bergmann, A., Gonen, H., Ciechanover, A. & Steller, H. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nature Cell Biol. 4, 432–438 (2002).

    CAS  PubMed  Google Scholar 

  35. 35

    Wilson, R. et al. The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nature Cell Biol. 4, 445–450 (2002).

    CAS  PubMed  Google Scholar 

  36. 36

    Ryoo, H. D., Gorenc, T. & Steller, H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev. Cell 7, 491–501 (2004). This study elucidates a mechanism whereby apoptotic cells activate signalling cascades for compensatory proliferation.

    CAS  PubMed  Google Scholar 

  37. 37

    Lee, T. V. et al. Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation. PLoS Genet. 7, e1002261 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Ditzel, M. et al. Inactivation of effector caspases through nondegradative polyubiquitylation. Mol. Cell 32, 540–553 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Eckelman, B. P. & Salvesen, G. S. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J. Biol. Chem. 281, 3254–3260 (2006).

    CAS  PubMed  Google Scholar 

  40. 40

    White, K. et al. Genetic control of programmed cell death in Drosophila. Science 264, 677–683 (1994). This work reports the discoveryof the first IAP antagonist, Reaper, which regulates apoptosis in D. melanogaster.

    CAS  PubMed  Google Scholar 

  41. 41

    Grether, M. E., Abrams, J. M., Agapite, J., White, K. & Steller, H. The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev. 9, 1694–1708 (1995).

    CAS  PubMed  Google Scholar 

  42. 42

    Chen, P., Nordstrom, W., Gish, B. & Abrams, J. M. grim, a novel cell death gene in Drosophila. Genes Dev. 10, 1773–1782 (1996).

    CAS  PubMed  Google Scholar 

  43. 43

    Shi, Y. A conserved tetrapeptide motif: potentiating apoptosis through IAP-binding. Cell Death Differ. 9, 93–95 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    White, K., Tahaoglu, E. & Steller, H. Cell killing by the Drosophila gene reaper. Science 271, 805–807 (1996).

    CAS  PubMed  Google Scholar 

  45. 45

    Sandu, C., Ryoo, H. D. & Steller, H. Drosophila IAP antagonists form multimeric complexes to promote cell death. J. Cell Biol. 190, 1039–1052 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Bergmann, A., Agapite, J., McCall, K. & Steller, H. The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 95, 331–341 (1998). This work reports the discoveryof the IAP antagonist Hid, which regulates apoptosis in D. melanogaster.

    CAS  PubMed  Google Scholar 

  47. 47

    Bergmann, A., Tugentman, M., Shilo, B. Z. & Steller, H. Regulation of cell number by MAPK-dependent control of apoptosis: a mechanism for trophic survival signaling. Dev. Cell 2, 159–170 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Zhou, L. & Steller, H. Distinct pathways mediate UV-induced apoptosis in Drosophila embryos. Dev. Cell 4, 599–605 (2003).

    CAS  PubMed  Google Scholar 

  49. 49

    Steller, H. Regulation of apoptosis in Drosophila. Cell Death Differ. 15, 1132–1138 (2008).

    CAS  PubMed  Google Scholar 

  50. 50

    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 

  51. 51

    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). References 50 and 51 report the independent discovery of the mammalian IAP antagonist SMAC.

    CAS  PubMed  Google Scholar 

  52. 52

    Suzuki, Y. et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8, 613–621 (2001).

    CAS  PubMed  Google Scholar 

  53. 53

    Verhagen, A. M. et al. Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ. 14, 348–357 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Martins, L. M. et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24, 9848–9862 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Okada, H. et al. Generation and characterization of Smac/DIABLO-deficient mice. Mol. Cell. Biol. 22, 3509–3517 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Fulda, S. & Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nature Rev. Drug Discov. 11, 109–124 (2012).

    CAS  Google Scholar 

  57. 57

    Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007).

    CAS  Google Scholar 

  58. 58

    Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007).

    CAS  Google Scholar 

  59. 59

    Larisch, S. et al. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nature Cell Biol. 2, 915–921 (2000).

    CAS  PubMed  Google Scholar 

  60. 60

    Gottfried, Y., Rotem, A., Lotan, R., Steller, H. & Larisch, S. The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J. 23, 1627–1635 (2004). This study shows that XIAP is the biochemical target of ARTS.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Kissel, H. et al. The Sept4 septin locus is required for sperm terminal differentiation in mice. Dev. Cell 8, 353–364 (2005).

    CAS  PubMed  Google Scholar 

  62. 62

    Garcia-Fernandez, M. et al. Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes Dev. 24, 2282–2293 (2010). This work shows that ARTS regulates the survival of haematopoietic stem cells and tumour formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Fuchs, Y. et al. Sept4/ARTS regulates stem cell apoptosis and skin regeneration. Science 341, 286–289 (2013). This report shows that ARTS deletion increases numbers of hair follicle stem cells and results in improved skin regeneration.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Tang, H. L. et al. Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol. Biol. Cell 23, 2240–2252 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    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). This study elegantly demonstrates a non-apoptotic cell death programme in C. elegans that is morphologically conserved throughout evolution.

    CAS  PubMed  Google Scholar 

  66. 66

    Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    CAS  Google Scholar 

  67. 67

    Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Gorski, S. M. et al. A SAGE approach to discovery of genes involved in autophagic cell death. Curr. Biol. 13, 358–363 (2003).

    CAS  PubMed  Google Scholar 

  69. 69

    Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    McPhee, C. K., Logan, M. A., Freeman, M. R. & Baehrecke, E. H. Activation of autophagy during cell death requires the engulfment receptor Draper. Nature 465, 1093–1096 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Yin, V. P. & Thummel, C. S. A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila. Proc. Natl Acad. Sci. USA 101, 8022–8027 (2004).

    CAS  PubMed  Google Scholar 

  72. 72

    Jiang, C., Baehrecke, E. H. & Thummel, C. S. Steroid regulated programmed cell death during Drosophila metamorphosis. Development 124, 4673–4683 (1997).

    CAS  PubMed  Google Scholar 

  73. 73

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

    CAS  PubMed  Google Scholar 

  74. 74

    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  PubMed  Google Scholar 

  75. 75

    Jiang, C., Lamblin, A. F., Steller, H. & Thummel, C. S. A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Mol. Cell 5, 445–455 (2000).

    CAS  PubMed  Google Scholar 

  76. 76

    Akdemir, F. et al. Autophagy occurs upstream or parallel to the apoptosome during histolytic cell death. Development 133, 1457–1465 (2006).

    CAS  PubMed  Google Scholar 

  77. 77

    Denton, D. et al. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr. Biol. 19, 1741–1746 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    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  PubMed  Google Scholar 

  80. 80

    Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005). This report shows that BCL-2 not only functions as an anti-apoptotic protein but also inhibits autophagy by interacting with BECN1.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Borsos, E., Erdelyi, P. & Vellai, T. Autophagy and apoptosis are redundantly required for C. elegans embryogenesis. Autophagy 7, 557–559 (2011).

    CAS  PubMed  Google Scholar 

  82. 82

    Maiuri, M. C. et al. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 26, 2527–2539 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Zalckvar, E. et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 10, 285–292 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Eisenberg-Lerner, A., Bialik, S., Simon, H. U. & Kimchi, A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 16, 966–975 (2009).

    CAS  Google Scholar 

  85. 85

    Zhu, Y. et al. Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein Cell 1, 468–477 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Yousefi, S. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nature Cell Biol. 8, 1124–1132 (2006).

    CAS  Google Scholar 

  87. 87

    Pyo, J. O. et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J. Biol. Chem. 280, 20722–20729 (2005).

    CAS  PubMed  Google Scholar 

  88. 88

    Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).

    CAS  Google Scholar 

  89. 89

    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  PubMed  PubMed Central  Google Scholar 

  90. 90

    Shen, S., Kepp, O. & Kroemer, G. The end of autophagic cell death? Autophagy 8, 1–3 (2012).

    PubMed  Google Scholar 

  91. 91

    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 work coins the term 'necroptosis' and identifies a chemical inhibitor of this process.

    CAS  Google Scholar 

  92. 92

    Galluzzi, L., Kepp, O., Krautwald, S., Kroemer, G. & Linkermann, A. Molecular mechanisms of regulated necrosis. Semin. Cell Dev. Biol. 35, 24–32 (2014).

    CAS  PubMed  Google Scholar 

  93. 93

    Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003). This study shows the early biochemical events that are initiated by TNFR1 ligation and the existence of two sequential signalling complexes.

    CAS  Google Scholar 

  95. 95

    Fuchs, Y. et al. Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB. Dev. Cell 23, 611–623 (2012).

    CAS  PubMed  Google Scholar 

  96. 96

    Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).

    CAS  PubMed  Google Scholar 

  97. 97

    Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Wright, A. et al. Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev. Cell 13, 705–716 (2007).

    CAS  PubMed  Google Scholar 

  99. 99

    Hitomi, J. et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135, 1311–1323 (2008). This study examines necroptosis and apoptosis using a systems biology approach, which elucidates the molecular switch between these two processes.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Varfolomeev, E. E. et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998).

    CAS  PubMed  Google Scholar 

  101. 101

    Yeh, W. C. et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279, 1954–1958 (1998).

    CAS  PubMed  Google Scholar 

  102. 102

    Yeh, W. C. et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12, 633–642 (2000).

    CAS  PubMed  Google Scholar 

  103. 103

    Oberst, A. et al. Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).

    CAS  Google Scholar 

  105. 105

    Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).

    CAS  Google Scholar 

  107. 107

    Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189–1202 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    CAS  Google Scholar 

  109. 109

    Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009). References 108–110 independently report the crucial role of RIPK3 in the regulation of necroptosis. Using various methods, the authors show that RIPK3 binds to RIPK1 and triggers the necroptotic programme.

    CAS  Google Scholar 

  111. 111

    Degterev, A. & Yuan, J. Expansion and evolution of cell death programmes. Nature Rev. Mol. Cell Biol. 9, 378–390 (2008).

    CAS  Google Scholar 

  112. 112

    Christofferson, D. E. & Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22, 263–268 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012). This is an elegant study showing that MLKL lies downstream of RIPK3 and is a crucial component of the necroptotic machinery.

    CAS  Google Scholar 

  114. 114

    Xie, T. et al. Structural insights into RIP3-mediated necroptotic signaling. Cell Rep. 5, 70–78 (2013).

    CAS  PubMed  Google Scholar 

  115. 115

    Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).

    CAS  Google Scholar 

  116. 116

    Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

    CAS  Google Scholar 

  117. 117

    Chen, X. et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121 (2014).

    CAS  Google Scholar 

  118. 118

    Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nature Cell Biol. 16, 55–65 (2014).

    CAS  Google Scholar 

  119. 119

    Wu, J. et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 23, 994–1006 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Mocarski, E. S., Kaiser, W. J., Livingston-Rosanoff, D., Upton, J. W. & Daley-Bauer, L. P. True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity. J. Immunol. 192, 2019–2026 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Mack, C., Sickmann, A., Lembo, D. & Brune, W. Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein. Proc. Natl Acad. Sci. USA 105, 3094–3099 (2008).

    CAS  Google Scholar 

  122. 122

    Skaletskaya, A. et al. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc. Natl Acad. Sci. USA 98, 7829–7834 (2001).

    CAS  PubMed  Google Scholar 

  123. 123

    Upton, J. W., Kaiser, W. J. & Mocarski, E. S. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe 7, 302–313 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Bonnet, M. C. et al. The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572–582 (2011).

    CAS  Google Scholar 

  125. 125

    Kovalenko, A. et al. Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J. Exp. Med. 206, 2161–2177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Gunther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Mahoney, D. J. et al. Both cIAP1 and cIAP2 regulate TNFα -mediated NF-κB activation. Proc. Natl Acad. Sci. USA 105, 11778–11783 (2008).

    CAS  Google Scholar 

  128. 128

    Darding, M. & Meier, P. IAPs: guardians of RIPK1. Cell Death Differ. 19, 58–66 (2012).

    CAS  PubMed  Google Scholar 

  129. 129

    Zarnegar, B. J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nature Immunol. 9, 1371–1378 (2008).

    CAS  Google Scholar 

  130. 130

    Tenev, T. et al. The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol. Cell 43, 432–448 (2011).

    CAS  Google Scholar 

  131. 131

    Feoktistova, M. et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43, 449–463 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Ravichandran, K. S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nature Rev. Immunol. 7, 964–974 (2007).

    CAS  Google Scholar 

  134. 134

    Suzuki, J., Denning, D. P., Imanishi, E., Horvitz, H. R. & Nagata, S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341, 403–406 (2013).

    CAS  PubMed  Google Scholar 

  135. 135

    Chen, Y. Z., Mapes, J., Lee, E. S., Skeen-Gaar, R. R. & Xue, D. Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes apoptosis and phosphatidylserine externalization. Nature Commun. 4, 2726 (2013). The elegant work described in references 134 and 135 shows that XK-related protein 8 and CED-8 promote apoptosis and phosphatidylserine exposure.

    Google Scholar 

  136. 136

    Birnbaum, K. D. & Sanchez Alvarado, A. Slicing across kingdoms: regeneration in plants and animals. Cell 132, 697–710 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Huh, J. R., Guo, M. & Hay, B. A. Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role. Curr. Biol. 14, 1262–1266 (2004).

    CAS  PubMed  Google Scholar 

  138. 138

    Perez-Garijo, A., Martin, F. A. & Morata, G. Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila. Development 131, 5591–5598 (2004). This work, together with references 36 and 137, elucidates the mechanism whereby apoptotic cells activate signalling cascades for compensatory proliferation.

    CAS  PubMed  Google Scholar 

  139. 139

    Bergmann, A. & Steller, H. Apoptosis, stem cells, and tissue regeneration. Sci. Signal. 3, re8 (2010).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Morata, G., Shlevkov, E. & Perez-Garijo, A. Mitogenic signaling from apoptotic cells in Drosophila. Dev. Growth Differ. 53, 168–176 (2011).

    Google Scholar 

  141. 141

    Bosch, M., Serras, F., Martin-Blanco, E. & Baguna, J. JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs. Dev. Biol. 280, 73–86 (2005).

    CAS  PubMed  Google Scholar 

  142. 142

    Perez-Garijo, A., Shlevkov, E. & Morata, G. The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc. Development 136, 1169–1177 (2009).

    CAS  PubMed  Google Scholar 

  143. 143

    Kondo, S., Senoo-Matsuda, N., Hiromi, Y. & Miura, M. DRONC coordinates cell death and compensatory proliferation. Mol. Cell. Biol. 26, 7258–7268 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    McEwen, D. G. & Peifer, M. Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development 132, 3935–3946 (2005).

    CAS  PubMed  Google Scholar 

  145. 145

    Shlevkov, E. & Morata, G. A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ. 19, 451–460 (2012).

    CAS  PubMed  Google Scholar 

  146. 146

    Warner, S. J., Yashiro, H. & Longmore, G. D. The Cdc42/Par6/aPKC polarity complex regulates apoptosis-induced compensatory proliferation in epithelia. Curr. Biol. 20, 677–686 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Bergantinos, C., Corominas, M. & Serras, F. Cell death-induced regeneration in wing imaginal discs requires JNK signalling. Development 137, 1169–1179 (2010).

    CAS  PubMed  Google Scholar 

  148. 148

    Smith-Bolton, R. K., Worley, M. I., Kanda, H. & Hariharan, I. K. Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. Dev. Cell 16, 797–809 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Fan, Y. & Bergmann, A. Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev. Cell 14, 399–410 (2008). This report indicates that compensatory proliferation is instructed in a distinct manner in differentiating and proliferating cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Chera, S. et al. Apoptotic cells provide an unexpected source of Wnt3 signaling to drive Hydra head regeneration. Dev. Cell 17, 279–289 (2009).

    CAS  PubMed  Google Scholar 

  151. 151

    Chera, S., Ghila, L., Wenger, Y. & Galliot, B. Injury-induced activation of the MAPK/CREB pathway triggers apoptosis-induced compensatory proliferation in hydra head regeneration. Dev. Growth Differ. 53, 186–201 (2011).

    CAS  PubMed  Google Scholar 

  152. 152

    Petersen, C. P. & Reddien, P. W. A wound-induced Wnt expression program controls planarian regeneration polarity. Proc. Natl Acad. Sci. USA 106, 17061–17066 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Adell, T., Salo, E., Boutros, M. & Bartscherer, K. Smed-Evi/Wntless is required for β-catenin-dependent and -independent processes during planarian regeneration. Development 136, 905–910 (2009).

    CAS  PubMed  Google Scholar 

  154. 154

    Gurley, K. A., Rink, J. C. & Sanchez Alvarado, A. β-catenin defines head versus tail identity during planarian regeneration and homeostasis. Science 319, 323–327 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Rink, J. C., Gurley, K. A., Elliott, S. A. & Sanchez Alvarado, A. Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science 326, 1406–1410 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Schnapp, E., Kragl, M., Rubin, L. & Tanaka, E. M. Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation and cartilage induction during axolotl tail regeneration. Development 132, 3243–3253 (2005).

    CAS  PubMed  Google Scholar 

  157. 157

    Tseng, A. S., Adams, D. S., Qiu, D., Koustubhan, P. & Levin, M. Apoptosis is required during early stages of tail regeneration in Xenopus laevis. Dev. Biol. 301, 62–69 (2007).

    CAS  PubMed  Google Scholar 

  158. 158

    Gauron, C. et al. Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. Sci. Rep. 3, 2084 (2013).

    PubMed  PubMed Central  Google Scholar 

  159. 159

    Nishina, T. et al. Interleukin-11 links oxidative stress and compensatory proliferation. Sci. Signal. 5, ra5 (2012).

    PubMed  Google Scholar 

  160. 160

    Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Li, F. et al. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal. 3, ra13 (2010).

    PubMed  PubMed Central  Google Scholar 

  162. 162

    Kurtova, A. V. et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517, 209–213 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nature Med. 17, 860–866 (2011). References 162 and 163 stress the importance of compensatory proliferation in tumorigenesis and as a source of potential targets for tumour therapy.

    CAS  PubMed  Google Scholar 

  164. 164

    Perez-Garijo, A., Fuchs, Y. & Steller, H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. eLife 2, e01004 (2013). This study shows that apoptotic cells can secrete Eiger or TNF ligands to induce cell death in neighbouring cells, leading to cohort cell death.

    PubMed  PubMed Central  Google Scholar 

  165. 165

    Lindner, G. et al. Analysis of apoptosis during hair follicle regression (catagen). Am. J. Pathol. 151, 1601–1617 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Biton, S. & Ashkenazi, A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling. Cell 145, 92–103 (2011).

    CAS  Google Scholar 

  167. 167

    Nelson, C. M. et al. Tumor necrosis factor-α is produced by dying retinal neurons and is required for Müller glia proliferation during zebrafish retinal regeneration. J. Neurosci. 33, 6524–6539 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Pellettieri, J. et al. Cell death and tissue remodeling in planarian regeneration. Dev. Biol. 338, 76–85 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Takeishi, A. et al. Homeostatic epithelial renewal in the gut is required for dampening a fatal systemic wound response in Drosophila. Cell Rep. 3, 919–930 (2013).

    CAS  PubMed  Google Scholar 

  170. 170

    Hei, T. K., Zhou, H., Chai, Y., Ponnaiya, B. & Ivanov, V. N. Radiation induced non-targeted response: mechanism and potential clinical implications. Curr. Mol. Pharmacol. 4, 96–105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Prise, K. M. & O'Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. Nature Rev. Cancer 9, 351–360 (2009).

    CAS  Google Scholar 

  172. 172

    Ellis, R. E., Yuan, J. Y. & Horvitz, H. R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698 (1991).

    CAS  PubMed  Google Scholar 

  173. 173

    Suzanne, M. & Steller, H. Shaping organisms with apoptosis. Cell Death Differ. 20, 669–675 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Peterson, J. S., Barkett, M. & McCall, K. Stage-specific regulation of caspase activity in Drosophila oogenesis. Dev. Biol. 260, 113–123 (2003).

    CAS  PubMed  Google Scholar 

  175. 175

    Monier, B. et al. Apico-basal forces exerted by apoptotic cells drive epithelium folding. Nature 518, 245–248 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Blum, E. S., Abraham, M. C., Yoshimura, S., Lu, Y. & Shaham, S. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335, 970–973 (2012).

    CAS  PubMed  Google Scholar 

  177. 177

    Osterloh, J. M. et al. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337, 481–484 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Yacobi-Sharon, K., Namdar, Y. & Arama, E. Alternative germ cell death pathway in Drosophila involves HtrA2/Omi, lysosomes, and a caspase-9 counterpart. Dev. Cell 25, 29–42 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Y. Fox for help with the figures and F. Kol for ongoing support. H.S. is an investigator with the Howard Hughes Medical Institute and is supported by the US National Institutes of Health grant RO1GM60124. Y.F. is supported by the Deloro Career Advancement Chair and the Alon Fellowship.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Yaron Fuchs or Hermann Steller.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Initiator caspases

Caspases that cleave inactive forms of executioner caspases.

Executioner caspases

Caspases that cleave various cellular proteins, often leading to apoptosis.

Apoptosome

A protein platform that is formed during apoptosis. This platform comprises cytochrome c that has translocated from the mitochondria to the cytoplasm and apoptotic protease- activating factor 1 (APAF1).

Mitochondrial outer membrane permeabilization

(MOMP). An event regulated by the BCL-2 protein family that is considered to be the 'point of no return' at which the cell commits to apoptosis.

Death-inducing signalling complex

(DISC). A protein platform formed by death receptors that can drive apoptosis.

Baculovirus IAP repeat domain

(BIR domain). A domain present in inhibitor of apoptosis proteins (IAPs) that can bind to caspases as well as to pro-apoptotic factors such as IAP antagonists.

Hair follicle stem cells

(HFSCs). Adult stem cells that are normally situated in a niche called the bulge and that function to replenish the hair follicle.

Linker cell

A migratory cell of the Caenorhabditis elegans male gonad that dies in a non-apoptotic, caspase- independent manner.

Autophagic cell death

A reported mode of programmed cell death that is associated with the presence of autophagosomes and that depends on autophagy-related proteins.

Necrostatin 1

A potent and selective inhibitor of necroptosis that was originally reported as a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in the necroptosis pathway.

Damage-associated molecular patterns

(DAMPs; also known as alarmins). Molecules that are released by stressed cells and that function as endogenous danger signals to initiate and propagate the inflammatory response.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fuchs, Y., Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol 16, 329–344 (2015). https://doi.org/10.1038/nrm3999

Download citation

Further reading

Search

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