Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival

Abstract

Caspase 8 can initiate apoptosis, but it also has non-apoptotic roles; for example, it is required for embryonic development and immune cell proliferation. Recent work has indicated that the requirement for caspase 8 in development and immune cell proliferation is defined by suppression of receptor-interacting protein kinase 3 (RIPK3), a kinase that triggers an alternative form of cell death called programmed necrosis. Interestingly, these recent findings can be reconciled with earlier work on the non-apoptotic roles of caspase 8.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Activation of caspase 8 by homodimerization and heterodimerization.
Figure 2: Recruitment of caspase 8 and FLIP to a RIPK1-containing complex determines cell fate.

Similar content being viewed by others

References

  1. Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827 (1996).

    CAS  PubMed  Google Scholar 

  2. Wilson, N. S., Dixit, V. & Ashkenazi, A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nature Immunol. 10, 348–355 (2009).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).

    CAS  PubMed  Google Scholar 

  5. Takahashi, T. et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76, 969–976 (1994).

    CAS  PubMed  Google Scholar 

  6. Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Pellegrini, M., Belz, G., Bouillet, P. & Strasser, A. Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc. Natl Acad. Sci. USA 100, 14175–14180 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. Zhang, J., Cado, D., Chen, A., Kabra, N. H. & Winoto, A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998).

    CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. Zhang, Y. et al. Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis. J. Immunol. 175, 3033–3044 (2005).

    CAS  PubMed  Google Scholar 

  14. Imtiyaz, H. Z. et al. The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells. J. Immunol. 176, 6852–6861 (2006).

    CAS  PubMed  Google Scholar 

  15. Salmena, L. et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 17, 883–895 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Beisner, D. R., Ch'en, I. L., Kolla, R. V., Hoffmann, A. & Hedrick, S. M. Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J. Immunol. 175, 3469–3473 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Hu, W. H., Johnson, H. & Shu, H. B. Activation of NF-κB by FADD, casper, and caspase-8. J. Biol. Chem. 275, 10838–10844 (2000).

    CAS  PubMed  Google Scholar 

  19. Golks, A., Brenner, D., Krammer, P. H. & Lavrik, I. N. The c-FLIP–NH2 terminus (p22-FLIP) induces NF-κB activation. J. Exp. Med. 203, 1295–1305 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Dohrman, A. et al. Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-κB activation. J. Immunol. 174, 5270–5278 (2005).

    CAS  PubMed  Google Scholar 

  21. Helfer, B. et al. Caspase-8 promotes cell motility and calpain activity under nonapoptotic conditions. Cancer Res. 66, 4273–4278 (2006).

    CAS  PubMed  Google Scholar 

  22. Rajput, A. et al. RIG-I RNA helicase activation of IRF3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein. Immunity 34, 340–351 (2011).

    CAS  PubMed  Google Scholar 

  23. 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 

  24. Alappat, E. C. et al. Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities. Mol. Cell 19, 321–332 (2005).

    CAS  PubMed  Google Scholar 

  25. Hua, Z. C., Sohn, S. J., Kang, C., Cado, D. & Winoto, A. A function of Fas-associated death domain protein in cell cycle progression localized to a single amino acid at its C-terminal region. Immunity 18, 513–521 (2003).

    CAS  PubMed  Google Scholar 

  26. Zhang, J., Kabra, N. H., Cado, D., Kang, C. & Winoto, A. FADD-deficient T cells exhibit a disaccord in regulation of the cell cycle machinery. J. Biol. Chem. 276, 29815–29818 (2001).

    CAS  PubMed  Google Scholar 

  27. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chem. Biol. 4, 313–321 (2008).

    CAS  Google Scholar 

  29. 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 

  30. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).

    CAS  PubMed  Google Scholar 

  31. 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  PubMed  Google Scholar 

  32. Zhang, H. et al. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471, 373–376 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 

  34. Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wajant, H. & Scheurich, P. TNFR1-induced activation of the classical NF-κB pathway. FEBS J. 278, 862–876 (2011).

    CAS  PubMed  Google Scholar 

  36. O'Donnell, M. A. & Ting, A. T. RIP1 comes back to life as a cell death regulator in TNFR1 signaling. FEBS J. 278, 877–887 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K. & Tschopp, J. NF-κB signals induce the expression of c-FLIP. Mol. Cell. Biol. 21, 5299–5305 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    CAS  PubMed  Google Scholar 

  39. Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

    CAS  PubMed  Google Scholar 

  40. 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 

  41. 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  PubMed  Google Scholar 

  42. Ch'en, I. L. et al. Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc. Natl Acad. Sci. USA 105, 17463–17468 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ch'en, I. L., Tsau, J. S., Molkentin, J. D., Komatsu, M. & Hedrick, S. M. Mechanisms of necroptosis in T cells. J. Exp. Med. 208, 633–641 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rosenberg, S., Zhang, H. & Zhang, J. FADD deficiency impairs early hematopoiesis in the bone marrow. J. Immunol. 186, 203–213 (2011).

    CAS  PubMed  Google Scholar 

  45. Boatright, K. M., Deis, C., Denault, J. B., Sutherlin, D. P. & Salvesen, G. S. Activation of caspases-8 and -10 by FLIPL . Biochem. J. 382, 651–657 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chang, D. W. et al. c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 21, 3704–3714 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Micheau, O. et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J. Biol. Chem. 277, 45162–45171 (2002).

    CAS  PubMed  Google Scholar 

  48. Pop, C. et al. FLIPL induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem. J. 433, 447–457 (2011).

    CAS  PubMed  Google Scholar 

  49. Kang, T. B. et al. Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J. Immunol. 181, 2522–2532 (2008).

    CAS  PubMed  Google Scholar 

  50. Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Feng, S. et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 19, 2056–2067 (2007).

    CAS  PubMed  Google Scholar 

  52. Lu, J. V. et al. Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity. Proc. Natl Acad. Sci. USA 108, 15312–15317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. O'Donnell, M. A. et al. Caspase 8 inhibits programmed necrosis by processing CYLD. Nature Cell Biol. (in the press).

  54. Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–521 (1997).

    CAS  PubMed  Google Scholar 

  55. Geserick, P. et al. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J. Cell Biol. 187, 1037–1054 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 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 

  57. Lemmers, B. et al. Essential role for caspase-8 in Toll-like receptors and NFκB signaling. J. Biol. Chem. 282, 7416–7423 (2007).

    CAS  PubMed  Google Scholar 

  58. Bidere, N., Snow, A. L., Sakai, K., Zheng, L. & Lenardo, M. J. Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-κB activation. Curr. Biol. 16, 1666–1671 (2006).

    CAS  PubMed  Google Scholar 

  59. Misra, R. S. et al. Caspase-8 and c-FLIPL associate in lipid rafts with NF-κB adaptors during T cell activation. J. Biol. Chem. 282, 19365–19374 (2007).

    CAS  PubMed  Google Scholar 

  60. Kataoka, T. & Tschopp, J. N-terminal fragment of c-FLIPL processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-κB signaling pathway. Mol. Cell. Biol. 24, 2627–2636 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Fernandes-Alnemri, T. et al. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc. Natl Acad. Sci. USA 93, 7464–7469 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167–170 (1995).

    CAS  PubMed  Google Scholar 

  64. Tanaka, M. et al. Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice. Immunity 10, 421–429 (1999).

    CAS  PubMed  Google Scholar 

  65. Jost, P. J. et al. Bcl10/Malt1 signaling is essential for TCR-induced NF-κB activation in thymocytes but dispensable for positive or negative selection. J. Immunol. 178, 953–960 (2007).

    CAS  PubMed  Google Scholar 

  66. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

    CAS  PubMed  Google Scholar 

  67. Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nature Immunol. 3, 830–835 (2002).

    CAS  Google Scholar 

  68. Zhang, N. & He, Y. W. An essential role for c-FLIP in the efficient development of mature T lymphocytes. J. Exp. Med. 202, 395–404 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang, H. et al. A role for cFLIP in B cell proliferation and stress MAPK regulation. J. Immunol. 182, 207–215 (2009).

    CAS  PubMed  Google Scholar 

  70. Imtiyaz, H. Z. et al. The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells. J. Immunol. 176, 6852–6861 (2006).

    CAS  PubMed  Google Scholar 

  71. Kaiser, W. J. & Offermann, M. K. Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J. Immunol. 174, 4942–4952 (2005).

    CAS  PubMed  Google Scholar 

  72. Weber, A. et al. Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ. 17, 942–951 (2010).

    CAS  PubMed  Google Scholar 

  73. Ben Moshe, T. et al. Role of caspase-8 in hepatocyte response to infection and injury in mice. Hepatology 45, 1014–1024 (2007).

    CAS  PubMed  Google Scholar 

  74. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).

    CAS  PubMed  Google Scholar 

  75. Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).

    CAS  PubMed  Google Scholar 

  76. Pop, C. & Salvesen, G. S. Human caspases: activation, specificity, and regulation. J. Biol. Chem. 284, 21777–21781 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003).

    CAS  PubMed  Google Scholar 

  78. Pop, C., Fitzgerald, P., Green, D. R. & Salvesen, G. S. Role of proteolysis in caspase-8 activation and stabilization. Biochemistry 46, 4398–4407 (2007).

    CAS  PubMed  Google Scholar 

  79. Oberst, A. et al. Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation. J. Biol. Chem. 285, 16632–16642 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hughes, M. A. et al. Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival. Mol. Cell 35, 265–279 (2009).

    CAS  PubMed  Google Scholar 

  81. Yu, J. W., Jeffrey, P. D. & Shi, Y. Mechanism of procaspase-8 activation by c-FLIPL . Proc. Natl Acad. Sci. USA 106, 8169–8174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nature Cell Biol. 11, 123–132 (2009).

    CAS  PubMed  Google Scholar 

  83. Haas, T. L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).

    CAS  PubMed  Google Scholar 

  84. Blonska, M. et al. TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation. J. Biol. Chem. 280, 43056–43063 (2005).

    CAS  PubMed  Google Scholar 

  85. Jin, Z. et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137, 721–735 (2009).

    CAS  PubMed  Google Scholar 

  86. Newton, K. et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 134, 668–678 (2008).

    CAS  PubMed  Google Scholar 

  87. Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by ALSAC/St. Jude, and by grants from the US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Douglas R. Green.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Douglas R. Green's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oberst, A., Green, D. It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nat Rev Mol Cell Biol 12, 757–763 (2011). https://doi.org/10.1038/nrm3214

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3214

This article is cited by

Search

Quick links

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