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.

  • Review Article
  • Published:

Caspases at the crossroads of immune-cell life and death

Key Points

  • Caspases are intracellular proteases that are divided into two subfamilies depending on whether they activate inflammation or apoptotic programmed cell death. However apoptotic caspases, particularly caspase-8 have recently been implicated in other immune processes and even cell survival.

  • Mice deficient in FAS-associated via death domain (FADD), cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) or caspase-8 have a similar embryonic lethal phenotype that is not clearly related to their function in apoptosis.

  • Caspase-8 also promotes differentiation of early haematopoietic precursors and monocytes.

  • In mature lymphocytes, it seems that FADD promotes cell division, whereas caspase-8 promotes post-activation cell survival. Conversely, inhibition of caspase-8 expression can predispose cells to die by non-apoptotic mechanisms.

  • A biochemical link between caspase-8 activation during immune-cell activation and a protein complex that activates nuclear factor-κB has been proposed.

  • Viral proteins that inhibit caspases might limit antiviral immune responses in addition to blocking virus-induced cell death.

  • Caspase inhibitors might modulate immune function in new ways, as well as blocking caspase-dependent cell death.

Abstract

Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death.

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: Extrinsic and pathways of apoptosis.
Figure 2: Checkpoints where caspases and related adaptor proteins negatively or positively regulate lymphocyte proliferation, differentiation and survival.
Figure 3: Caspases in mammalian and Drosophila nuclear factor-κB induction.

Similar content being viewed by others

References

  1. Boyce, M., Degterev, A. & Yuan, J. Caspases: an ancient cellular sword of Damocles. Cell Death Differ. 11, 29–37 (2004).

    CAS  PubMed  Google Scholar 

  2. Creagh, E. M., Conroy, H. & Martin, S. J. Caspase-activation pathways in apoptosis and immunity. Immunol. Rev. 193, 10–21 (2003).

    CAS  PubMed  Google Scholar 

  3. Nicholson, D. & Thornberry, N. Caspases: killer proteases. Trends Biochem. Sci. 22, 299–306 (1997).

    CAS  PubMed  Google Scholar 

  4. Martinon, F. & Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117, 561–574 (2004).

    CAS  PubMed  Google Scholar 

  5. Leulier, F., Rodriguez, A., Khush, R. S., Abrams, J. M. & Lemaitre, B. The Drosophila caspase Dredd is required to resist gram-negative bacterial infection. EMBO Rep. 1, 353–358 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Strasser, A. The role of BH3-only proteins in the immune system. Nature Rev. Immunol. 5, 189–200 (2005).

    CAS  Google Scholar 

  8. Acehan, D. et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell 9, 423–432 (2002).

    CAS  PubMed  Google Scholar 

  9. Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003). This report found that initiator caspases such as caspase-8 could become enzymatically active without undergoing autocatalytic cleavage.

    CAS  PubMed  Google Scholar 

  10. Peter, M. E. & Krammer, P. H. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35 (2003).

    CAS  PubMed  Google Scholar 

  11. Siegel, R. M. et al. SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. J. Cell Biol. 167, 735–744 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Martin, D. A., Siegel, R. M., Zheng, L. & Lenardo, M. J. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHα1) death signal. J. Biol. Chem. 273, 4345–4349 (1998).

    CAS  PubMed  Google Scholar 

  13. Tschopp, J., Irmler, M. & Thome, M. Inhibition of fas death signals by FLIPs. Curr. Opin. Immunol. 10, 552–558 (1998).

    CAS  PubMed  Google Scholar 

  14. 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 

  15. Scaffidi, C., Schmitz, I., Krammer, P. H. & Peter, M. E. The role of c-FLIP in modulation of CD95-induced apoptosis. J. Biol. Chem. 274, 1541–1548 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Siegel, R. M., Chan, F. K., Chun, H. J. & Lenardo, M. J. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nature Immunol. 1, 469–474 (2000).

    CAS  Google Scholar 

  18. Abbas, A. K. Die and let live: eliminating dangerous lymphocytes. Cell 84, 655–657 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  20. 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 

  21. Straus, S. E., Sneller, M., Lenardo, M. J., Puck, J. M. & Strober, W. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann. Intern. Med. 130, 591–601 (1999).

    CAS  PubMed  Google Scholar 

  22. Fleisher, T. A. et al. The autoimmune lymphoproliferative syndrome. A disorder of human lymphocyte apoptosis. Clin. Rev. Allergy Immunol. 20, 109–120 (2001).

    CAS  PubMed  Google Scholar 

  23. Fisher, G. H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995).

    CAS  PubMed  Google Scholar 

  24. Hao, Z., Hampel, B., Yagita, H. & Rajewsky, K. T cell-specific ablation of Fas leads to Fas ligand-mediated lymphocyte depletion and inflammatory pulmonary fibrosis. J. Exp. Med. 199, 1355–1365 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cohen, P. L. & Eisenberg, R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu. Rev. Immunol. 9, 243–269 (1991).

    CAS  PubMed  Google Scholar 

  26. 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 

  27. 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). Using RAG1-deficient–FADD-deficient chimeric mice, this report found a non-apoptotic function for the FADD adaptor protein in lymphocyte development and T-cell proliferation.

    CAS  PubMed  Google Scholar 

  28. 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 

  29. Chau, H. et al. Cellular FLICE-inhibitory protein is required for T cell survival and cycling. J. Exp. Med. 202, 405–413 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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). This study showed a role for FADD in peripheral T-cell homeostasis through conditional deletion of a transgene encoding a FADD–GFP fusion protein.

    CAS  PubMed  Google Scholar 

  31. 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 

  32. 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 

  33. Newton, K., Harris, A. W. & Strasser, A. FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. EMBO J. 19, 931–941 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kang, T. B. et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 173, 2976–2984 (2004).

    CAS  PubMed  Google Scholar 

  35. Pellegrini, M. et al. FADD and Caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells. Blood 106, 1581–1589 (2005). References 34 and 35 showed a role for caspase-8 in early haematopoiesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Palmer, E. Negative selection-clearing out the bad apples from the T-cell repertoire. Nature Rev. Immunol. 3, 383–391 (2003).

    CAS  Google Scholar 

  37. Villunger, A. et al. Negative selection of semimature CD4+8HSA+ thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling. Proc. Natl Acad. Sci. USA 101, 7052–7057 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Doerfler, P., Forbush, K. A. & Perlmutter, R. M. Caspase enzyme activity is not essential for apoptosis during thymocyte development. J. Immunol. 164, 4071–4079 (2000).

    CAS  PubMed  Google Scholar 

  39. Alam, A., Cohen, L. Y., Aouad, S. & Sekaly, R. P. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 190, 1879–1890 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kennedy, N. J., Kataoka, T., Tschopp, J. & Budd, R. C. Caspase activation is required for T cell proliferation. J. Exp. Med. 190, 1891–1896 (1999). References 39 and 40 first indicated a role for caspase enzymatic activity in mature T-cell proliferation.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Boissonnas, A. et al. Differential requirement of caspases during naive T cell proliferation. Eur. J. Immunol. 32, 3007–3015 (2002).

    CAS  PubMed  Google Scholar 

  42. 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 

  43. Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002). This study described an inherited immunodeficiency syndrome and lymphocyte activation defects linked to a caspase-8 mutation.

    CAS  PubMed  Google Scholar 

  44. Wang, J. et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98, 47–58 (1999).

    CAS  PubMed  Google Scholar 

  45. Newton, K., Harris, A. W., Bath, M. L., Smith, K. G. C. & Strasser, A. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17, 706–718 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zornig, M., Hueber, A. O. & Evan, G. p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice. Curr. Biol. 8, 467–470 (1998).

    CAS  PubMed  Google Scholar 

  47. Walsh, C. M. et al. A role for FADD in T cell activation and development. Immunity 8, 439–449 (1998).

    CAS  PubMed  Google Scholar 

  48. Beisner, D. R., Chu, I. H., Arechiga, A. F., Hedrick, S. M. & Walsh, C. M. The requirements for fas-associated death domain signaling in mature T cell activation and survival. J. Immunol. 171, 247–256 (2003).

    CAS  PubMed  Google Scholar 

  49. O'Reilly, L. A. et al. Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes. Cell Death Differ. 11, 724–736 (2004).

    CAS  PubMed  Google Scholar 

  50. 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 

  51. 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). This study indicated a role for FADD phosphorylation in cell-cycle progression in T cells.

    CAS  PubMed  Google Scholar 

  52. Wu, Z. et al. Viral FLIP impairs survival of activated T cells and generation of CD8+ T cell memory. J. Immunol. 172, 6313–23 (2004). The data presented in this paper indicate a role for a signalling pathway blocked by vFLIP in peripheral CD8+T-cell survival and the generation of CD8+ T-cell memory.

    CAS  PubMed  Google Scholar 

  53. Lens, S. M. et al. The caspase 8 inhibitor c-FLIPL modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes. Mol. Cell. Biol. 22, 5419–5433 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Salmena, L. & Hakem, R. Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. J. Exp. Med. 202, 727–732 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sehra, S. et al. A role for caspases in controlling IL-4 expression in T cells. J. Immunol. 174, 3440–3446 (2005).

    CAS  PubMed  Google Scholar 

  56. Silva, E. M. et al. Caspase-8 activity prevents type 2 cytokine responses and is required for protective T cell-mediated immunity against Trypanosoma cruzi infection. J. Immunol. 174, 6314–6321 (2005).

    CAS  PubMed  Google Scholar 

  57. Tseveleki, V. et al. Cellular FLIP (long isoform) overexpression in T cells drives Th2 effector responses and promotes immunoregulation in experimental autoimmune encephalomyelitis. J. Immunol. 173, 6619–6626 (2004).

    CAS  PubMed  Google Scholar 

  58. Wu, W. et al. Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation. J. Immunol. 172, 4724–4732 (2004).

    CAS  PubMed  Google Scholar 

  59. Olson, N. E., Graves, J. D., Shu, G. L., Ryan, E. J. & Clark, E. A. Caspase activity is required for stimulated B lymphocytes to enter the cell cycle. J. Immunol. 170, 6065–6072 (2003).

    CAS  PubMed  Google Scholar 

  60. 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). This report showed a role for caspase-8 in the activation of B cells by TLR ligands, without an apparent effect on activation of NF-κB.

    CAS  PubMed  Google Scholar 

  61. Woo, M. et al. Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Nature Immunol. 4, 1016–1022 (2003). This study indicated an inhibitory role for caspase-3 in cell-cycle progression of B cells.

    CAS  Google Scholar 

  62. Woo, M. et al. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12, 806–819 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sordet, O. et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood 100, 4446–4453 (2002).

    CAS  PubMed  Google Scholar 

  64. De Botton, S. et al. Platelet formation is the consequence of caspase activation within megakaryocytes. Blood 100, 1310–1317 (2002).

    CAS  PubMed  Google Scholar 

  65. Santambrogio, L. et al. Involvement of caspase-cleaved and intact adaptor protein 1 complex in endosomal remodeling in maturing dendritic cells. Nature Immunol. 6, 1020–1028 (2005).

    CAS  Google Scholar 

  66. Kataoka, T. et al. The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways. Curr. Biol. 10, 640–648 (2000).

    CAS  PubMed  Google Scholar 

  67. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004).

    CAS  Google Scholar 

  68. Lee, K. Y., D'Acquisto, F., Hayden, M. S., Shim, J. H. & Ghosh, S. PDK1 nucleates T cell receptor-induced signaling complex for NF-κB activation. Science 308, 114–118 (2005).

    CAS  PubMed  Google Scholar 

  69. Che, T. et al. MALT1/paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-κB activation. J. Biol. Chem. 279, 15870–15876 (2004).

    CAS  PubMed  Google Scholar 

  70. Su, H. et al. Requirement for caspase-8 in NF-κB activation by antigen receptor. Science 307, 1465–1468 (2005). This study showed defective NF-κB activation in multiple cell types deficient in caspase-8 or harbouring caspase-8 mutations, and indicated a direct association of caspase-8 with the CARMA1–BCL-10–MALT1 complex.

    CAS  PubMed  Google Scholar 

  71. Uren, A. G. et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967 (2000). This study identified MALT1 as a caspase-related protein with the potential to activate NF-κB.

    CAS  PubMed  Google Scholar 

  72. Arechiga, A. F. et al. Cutting edge: FADD is not required for antigen receptor-mediated NF-κB activation. J. Immunol. 175, 7800–7804 (2005).

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

    CAS  PubMed  Google Scholar 

  74. Li, M. & Beg, A. A. Induction of necrotic-like cell death by tumor necrosis factor a and caspase inhibitors: novel mechanism for killing virus-infected cells. J. Virol. 74, 7470–7477 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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). References 73–75 showed a role for caspases in protecting cells from non-apoptotic cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Choe, K. M., Lee, H. & Anderson, K. V. Drosophila peptidoglycan recognition protein LC (PGRP-LC) acts as a signal-transducing innate immune receptor. Proc. Natl Acad. Sci. USA 102, 1122–1126 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Stoven, S. et al. Caspase-mediated processing of the Drosophila NF-κB factor Relish. Proc. Natl Acad. Sci. USA 100, 5991–5996 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhou, R. et al. The role of ubiquitnation in Drosophila innate immunity. J. Biol. Chem. 280, 34048–34055 (2005).

    CAS  PubMed  Google Scholar 

  79. Chen, Z. J. Ubiquitin signalling in the NF-κB pathway. Nature Cell Biol. 7, 758–765 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  81. Wencker, D. et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J. Clin. Invest. 111, 1497–1504 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Stratton, G. A. Some preliminary experiments on vision without inversion of the retinal image. Psychol. Rev. 4, 611–617 (1896).

    Google Scholar 

  83. Thornberry, N. A. et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J. Biol. Chem. 272, 17907–17911 (1997). This study reports data that used a peptide-library screen to define the cleavage preferences for caspases.

    CAS  PubMed  Google Scholar 

  84. Dohrman, A. et al. Cellular FLIP long form augments caspase activity and death of T cells through heterodimerization with and activation of caspase-8. J. Immunol. 175, 311–318 (2005).

    CAS  PubMed  Google Scholar 

  85. Tu, S. et al. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nature Cell Biol. 8, 72–77 (2006). In this study, biotinylated caspase inhibitor peptides were used to identify the apical caspases in a number of different cell-death pathways.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank A. Bhandoola, Y.-W. He, M. Lenardo, N. Bidére, M. Lopes, C. Walsh, and J. Zhang for helpful discussions and sharing unpublished data; J. Muppidi for assistance with the figures, and members of my laboratory for critical review of the manuscript. This work was supported by the Intramural Research Program, NIAMS, National Institutes of Health.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Richard Siegel's laboratory

Glossary

Restimulation-induced cell death

(RICD). Cell death that occurrs after restimulation of activated lymphocytes through the antigen receptor. Use of RICD avoids using the confusing term activation-induced cell death, which has been used to refer to cell death occurring after primary activation as well as restimulation.

Autoimmune lymphoproliferative syndrome

A rare childhood disease that is characterized by lymphadenopathy, splenomegaly and autoimmunity, and that is associated with heterozygous CD95 mutations in 80% of cases. This disease is also known as Canale–Smith syndrome.

Dominant-negative protein

A defective variant of a protein that retains the ability to interact with other proteins but lacks enzymatic activity. A dominant-negative protein thereby distorts or competes with normal variants of the protein.

Negative selection

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self-peptide bound to self-MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

Hypogammaglobulinaemia

A condition marked by low levels of serum immunoglobulins that occurs in patients with many different primary immunodeficiencies.

Lymphopaenic host

A recipient mouse that is depleted of lymphocytes. This can be done experimentally by γ-irradiation or genetic ablation of either recombination-activating gene 1 (RAG1) or RAG2. Other lymphopaenic mice include severe combined immunodeficient mice, which lack all lymphocytes, and nude mice, which lack a thymus and therefore, T cells.

Ovalbumin-induced asthma model

An experimental model of human allergic asthma in which mice are first sensitized to, then challenged with, ovalbumin. This leads to airway hyper-reactivity, a cardinal feature of asthma in humans.

p21

p21 (also known as WAF1, CIP1 and CDKN1A) is a cell-cycle inhibitor that binds to and inhibits the activity of cyclin–CDK2 (cyclin-dependent kinase 2) and cyclin–CDK4 complexes, thereby functioning as a regulator of cell-cycle progression at the G1 phase of the cell cycle.

Lipid rafts

Specialized membrane domains that are enriched in cholesterol and glycosphingolipids, and proteins that function in signal transduction. Rafts are often equated with 'detergent-resistant membranes', which can be isolated by density-gradient centrifugation as a function of their high buoyancy.

K63-linked ubiquitylation

The addition of ubiquitin to lysine side chains of target proteins using the lysine at position 63 (K63) in ubiquitin. K63-linked ubiquitin-modified proteins function in DNA repair, the stress response, mitochondrial DNA inheritance and the targeting of certain proteins for endocytosis, unlike K48-linked chains which are the principal signal for targeting substrates for proteasomal degradation.

Jurkat T cell

A human leukaemic T-cell line used to study several aspects of T-cell biology and signalling, in particular, signal-transduction events initiated by the T-cell receptor.

Immunoprecipitated

Proteins that have been purified by binding to specific antibodies immobilized to a solid-phase support.

Small interfering RNA

(siRNA). Short (21-base pairs) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.

Autophagic-cell morphology

The electron microscopic appearance of cells marked by expanded double-walled phagocytic vesicles that are termed autophagosomes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Siegel, R. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6, 308–317 (2006). https://doi.org/10.1038/nri1809

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1809

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