Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) is an enzymatically inert homologue of caspase-8 that competes with caspase-8 for recruitment to the death-inducing signalling complex (DISC).
Paradoxically, cFLIP can also heterodimerize with caspase-8, which results in activation of the full-length caspase-8 protein.
Caspase-8 activity is necessary to initiate the activation of nuclear factor-κB (NF-κB) and to promote proliferation of T cells, and possibly other cell types. Increased expression of cFLIP can augment caspase-8 activity following T-cell receptor (TCR) ligation on T cells. This results in both increased proliferation, and also, ultimately, increased cell death.
cFLIP can associate with adaptor proteins such as tumour-necrosis-factor-receptor-associated factor 2 (TRAF2) that link to the NF-κB pathway. Therefore, increased expression of cFLIP might augment NF-κB activity in some situations, but it has also been reported to decrease NF-κB signalling following CD95 (also known as FAS) stimulation. The explanation for these disparate results is not certain at present.
T cells lacking cFLIP manifest decreased proliferation and survival. This might be related to decreased production of and response to interleukin-2 (IL-2) by the cFLIP-deficient T cells.
cFLIP might be crucial to effector function in many other cell types; for example, myeloid dendritic cells, which express high levels of cFLIP, are resistant to FAS-mediated cell death, and produce large amounts of several cytokines and mediate upregulation of CD80 and CD86 in response to CD95 ligation.
Cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) was originally identified as an inhibitor of death-receptor signalling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that both cFLIP and caspase-8 are required for the survival and proliferation of T cells following T-cell-receptor stimulation. This paradoxical finding launched new investigations of how these molecules might connect with signalling pathways that link to cell survival and growth following antigen-receptor activation. As discussed in this Review, insight gained from these studies indicates that cFLIP and caspase-8 form a heterodimer that ultimately links T-cell-receptor signalling to activation of nuclear factor-κB through a complex that includes B-cell lymphoma 10 (BCL-10), mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1) and receptor-interacting protein 1 (RIP1).
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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). One of the first descriptions of the ability of cFLIP L to activate full-length caspase-8.
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signalling complexes. Cell 114, 181–190 (2003).
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 signalling pathway. Mol. Cell. Biol. 24, 2627–2636 (2004). An important study showing that p43cFLIP can recruit TRAF2 more efficiently than cFLIP L . This might indicate that cFLIP L is an important caspase-8 substrate following T-cell activation.
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).
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).
Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–520 (1997). The original description of FLIP as a viral protein before the discovery of cellular FLIP.
Hu, S., Vincez, C., Buller, M. & Dixit, V. M. A novel family of viral death effector domain-containing molecules that inhibit both CD95 and tumour necrosis factor receptor -1-induced apoptosis. J. Biol. Chem. 272, 9621–9624 (1997).
Bertin, J. et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc. Natl Acad. Sci. USA 94, 1172–1176 (1997).
Hofmann, K. The modular nature of apoptotic signalling proteins. Cell Mol. Life Sci. 55, 1113–1128 (1999).
Searles, R. P., Bergquam, E. P., Axthelm, M. K. & Wong, S. W. Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. J. Virol. 73, 3040–3053 (1999).
Irmler, M. et al. Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195 (1997).
Shu, H. B., Halpin, D. R. & Goeddel, D. V. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6, 751–763 (1997).
Srinivasula, S. M. et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J. Biol. Chem. 272, 18542–18545 (1997).
Inohara, N., Koseki, T., Hu, Y., Chen, S. & Nunez, G. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc. Natl Acad. Sci. USA 94, 10717–10722 (1997).
Goltsev, Y. V. et al. CASH, a novel caspase homologue with death effector domains. J. Biol. Chem. 272, 19641–19644 (1997).
Han, D. K. et al. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc. Natl Acad. Sci. USA 94, 11333–11338 (1997).
Hu, S., Vincenz, C., Ni, J., Gentz, R. & Dixit, V. M. I-FLICE, a novel inhibitor of tumour necrosis factor receptor-1 and CD95-induced apoptosis. J. Biol. Chem. 272, 17255–17257 (1997).
Rasper, D. M. et al. Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Cell Death Differ. 5, 271–288 (1998).
Tschopp, J., Irmler, M. & Thome, M. Inhibition of fas death signals by FLIPs. Curr. Opin. Immunol. 10, 552–558. (1998).
Golks, A., Brenner, D., Fritsch, C., Krammer, P. H. & Lavrik, I. N. c-FLIPR, a new regulator of death receptor-induced apoptosis. J. Biol. Chem. 280, 14507–14513 (2005).
Poukkula, M. et al. Rapid turnover of c-FLIPshort is determined by its unique C-terminal tail. J. Biol. Chem. 280, 27345–27355 (2005).
Cohen, G. M. Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16 (1997). An excellent review of caspase structure and activation.
Krueger, A., Schmitz, I., Baumann, S., Krammer, P. H. & Kirchhoff, S. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signalling complex. J. Biol. Chem. 276, 20633–20640 (2001).
Micheau, O. et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signalling complex. J. Biol. Chem. 277, 45162–45171 (2002). An important description of cFLIP L as an activator of caspase-8.
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).
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 26–28 describe the requirement of caspase activity, and specifically caspase-8, for T cell activation.
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).
Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002).
Kataoka, T. et al. The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signalling pathways. Curr. Biol. 10, 640–648 (2000). The first demonstration that cFLIP could augment activation of ERK and NF-κB.
Kreuz, S. et al. NFκB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J. Cell Biol. 166, 369–380 (2004).
Legembre, P. et al. Induction of apoptosis and activation of NF-κB by CD95 require different signalling thresholds. EMBO Rep. 5, 1084–1089 (2004).
Barnhart, B. C. et al. CD95 ligand induces motility and invasiveness of apoptosis-resistant tumour cells. EMBO J. 23, 3175–3185 (2004).
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).
Alappat, E. C. et al. Phosphorylation of FADD at Serine 194 by CKIα regulates its nonapoptotic activities. Mol. Cell 19, 321–332 (2005).
Scaffidi, C. et al. Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase. J. Immunol. 164, 1236–1242 (2000).
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).
Yang, B. F., Xiao, C., Roa, W. H., Krammer, P. H. & Hao, C. Calcium/calmodulin-dependent protein kinase II regulation of c-FLIP expression and phosphorylation in modulation of Fas-mediated signalling in malignant glioma cells. J. Biol. Chem. 278, 7043–7050 (2003).
Higuchi, H. et al. Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. J. Biol. Chem. 278, 454–461 (2003).
Fukazawa, T. et al. Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells. Oncogene 20, 5225–5231 (2001).
Desbarats, J. et al. Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nature Cell Biol. 5, 118–125 (2003).
Davidson, S. M., Stephanou, A. & Latchman, D. S. FLIP protects cardiomyocytes from apoptosis induced by simulated ischemia/reoxygenation, as demonstrated by short hairpin-induced (shRNA) silencing of FLIP mRNA. J. Mol. Cell. Cardiol. 35, 1359–1364 (2003).
Bouchet, D. et al. Differential sensitivity of endothelial cells of various species to apoptosis induced by gene transfer of Fas ligand: role of FLIP levels. Mol. Med. 8, 612–623 (2002).
Marconi, A. et al. FLICE/caspase-8 activation triggers anoikis induced by β1-integrin blockade in human keratinocytes. J. Cell. Sci. 117, 5815–5823 (2004).
Maedler, K. et al. FLIP switches Fas-mediated glucose signalling in human pancreatic β cells from apoptosis to cell replication. Proc. Natl Acad. Sci. USA 99, 8236–8241 (2002).
Ashany, D., Savir, A., Bhardwaj, N. & Elkon, K. B. Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. J. Immunol. 163, 5303–5311 (1999).
Rescigno, M. et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1β, and the production of interferon-γ in the absence of IL-12 during DC-T cell cognate interaction. A new role for fas ligand in inflammatory responses. J. Exp. Med. 192, 1661–1668 (2000). An important demonstration that CD95 might provide activation signals rather than inducing cell death of DCs, because they express high levels of cFLIP.
Kiener, P. A. et al. Differential induction of apoptosis by Fas–Fas ligand interactions in human monocytes and macrophages. J. Exp. Med. 185, 1511–1516 (1997).
Kim, H., Whartenby, K. A., Georgantas, R. W., Wingard, J. & Civin, C. I. Human CD34+ hematopoietic stem/progenitor cells express high levels of FLIP and are resistant to Fas-mediated apoptosis. Stem Cells 20, 174–182 (2002).
Giampietri, C. et al. FLIP is expressed in mouse testis and protects germ cells from apoptosis. Cell Death Differ. 10, 175–184 (2003).
Yeh, J. H., Hsu, S. C., Han, S. H. & Lai, M. Z. Mitogen-activated protein kinase kinase antagonized Fas-associated death domain protein-mediated apoptosis by induced FLICE-inhibitory protein expression. J. Exp. Med. 188, 1795–1802 (1998).
Schlapbach, R. et al. TGF-β induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Eur. J. Immunol. 30, 3680–3688 (2000).
Qiao, L. et al. Bile acid regulation of C/EBPβ, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol. Cell. Biol. 23, 3052–3066 (2003).
Wang, W., Prince, C. Z., Mou, Y. & Pollman, M. J. Notch3 signalling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis. J. Biol. Chem. 277, 21723–21729 (2002).
Panka, D. J., Mano, T., Suhara, T., Walsh, K. & Mier, J. W. Phosphatidylinositol 3-kinase/Akt activity regulates c-FLIP expression in tumour cells. J. Biol. Chem. 276, 6893–6896 (2001).
Suhara, T., Mano, T., Oliveira, B. E. & Walsh, K. Phosphatidylinositol 3-kinase/Akt signalling controls endothelial cell sensitivity to Fas-mediated apoptosis via regulation of FLICE-inhibitory protein (FLIP). Circ. Res. 89, 13–19 (2001).
Nam, S. Y. et al. Upregulation of FLIPS by Akt, a possible inhibition mechanism of TRAIL-induced apoptosis in human gastric cancers. Cancer Sci. 94, 1066–1073 (2003).
Poulaki, V. et al. Regulation of Apo2L/tumour necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells. Am. J. Pathol. 161, 643–654 (2002).
Sade, H., Krishna, S. & Sarin, A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signalling in T cells. J. Biol. Chem. 279, 2937–2944 (2004).
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).
Kreuz, S., Siegmund, D., Scheurich, P. & Wajant, H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signalling. Mol. Cell. Biol. 21, 3964–3973 (2001).
Rao, A., Luo, C. & Hogan, P. G. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15, 707–747 (1997).
Volpert, O. V. et al. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nature Med. 8, 349–357 (2002).
Zaichuk, T. A. et al. Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J. Exp. Med. 199, 1513–1522 (2004).
Bartke, T. et al. p53 upregulates cFLIP, inhibits transcription of NF-κB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells. Oncogene 20, 571–580 (2001).
Inoue, H. et al. Adenoviral-mediated transfer of p53 gene enhances TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Int. J. Mol. Med. 14, 271–275 (2004).
Ricci, M. S. et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol. Cell. Biol. 24, 8541–8555 (2004).
Stassi, G. et al. Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. Nature Immunol. 1, 483–488 (2000).
Refaeli, Y., Van Parijs, L., London, C. A., Tschopp, J. & Abbas, A. K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8, 615–623 (1998).
Kovalovich, K. et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J. Biol. Chem. 276, 26605–26613 (2001).
Lee, S. W., Park, Y., Yoo, J. K., Choi, S. Y. & Sung, Y. C. Inhibition of TCR-induced CD8 T cell death by IL-12: regulation of Fas ligand and cellular FLIP expression and caspase activation by IL-12. J. Immunol. 170, 2456–2460 (2003).
Conticello, C. et al. IL-4 protects tumour cells from anti-CD95 and chemotherapeutic agents via upregulation of antiapoptotic proteins. J. Immunol. 172, 5467–5477 (2004).
Eslick, J. et al. IL-4 and IL-10 inhibition of spontaneous monocyte apoptosis is associated with Flip upregulation. Inflammation 28, 139–145 (2004).
Grassi, F. et al. Inhibition of CD95 apoptotic signalling by interferon-γ in human osteoarthritic chondrocytes is associated with increased expression of FLICE inhibitory protein. Arthritis Rheum. 50, 498–506 (2004).
Zhang, J. et al. IL-4 potentiates activated T cell apoptosis via an IL-2-dependent mechanism. J. Immunol. 170, 3495–3503 (2003).
Misra, R. S. et al. Effector CD4+ T cells generate intermediate caspase activity and cleavage of caspase-8 substrates. J. Immunol. 174, 3999–4009 (2005).
Alderson, M. R. et al. Fas transduces activation signals in normal human T lymphocytes. J. Exp. Med. 178, 2231–2235 (1993). The first study showing that CD95 can co-stimulate resting T cells.
Migone, T. S. et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell co-stimulator. Immunity 16, 479–492 (2002).
Watts, T. H. TNF/TNFR family members in co-stimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).
Salmena, L. et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 17, 883–895 (2003). The first description of a conditional Casp8 knockout mouse showing that caspase-8 is required for T-cell survival and activation.
Lens, S. M. A. 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).
Zhang, X. et al. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J. Exp. Med. 185, 1837–1849 (1997).
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).
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).
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). References 84 and 85 show the requirement of cFLIP for T-cell survival and activation.
Chau, H. et al. Cellular FLICE-inhibitory protein is required for T cell survival and cycling. J. Exp. Med. 202, 405–413 (2005).
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).
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).
Walsh, C. M. et al. A role for FADD in T cell activation and development. Immunity 8, 439–449 (1998).
Beisner, D. R., Chu, I. H., Arechiga, A. F., Hedrick, S. M. & Walsh, C. M. The requirements for Fas-associated death domain signalling in mature T cell activation and survival. J. Immunol. 171, 247–256 (2003).
Hueber, A. O., Zornig, M., Bernard, A. M., Chautan, M. & Evan, G. A dominant negative Fas-associated death domain protein mutant inhibits proliferation and leads to impaired calcium mobilization in both T-cells and fibroblasts. J. Biol. Chem. 275, 10453–10462 (2000).
Su, H. et al. Requirement for caspase-8 in NF-κB activation by antigen receptor. Science 307, 1465–1468 (2005). An important advance showing that the active caspase complex in effector T cells associates with BCL-10 and MALT1 to link to activation of NF-κB.
Kang, T. B. et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 173, 2976–2984 (2004).
Kirchhoff, S., Muller, W. W., Li-Weber, M. & Krammer, P. H. Upregulation of c-FLIPshort and reduction of activation-induced cell death in CD28-co-stimulated human T cells. Eur. J. Immunol. 30, 2765–2774 (2000).
Wu, Z. et al. Viral FLIP impairs survival of activated T cells and generation of CD8+ T cell memory. J. Immunol. 172, 6313–6323 (2004).
Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004). An excellent review of the CARD–MAGUK protein 1 (CARMA1)–BCL-10–MALT1 complex.
Perlman, H. et al. FLICE-inhibitory protein expression during macrophage differentiation confers resistance to Fas-mediated apoptosis. J. Exp. Med. 190, 1679–1688 (1999).
Willems, F. et al. Expression of c-FLIPL and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide. Blood 95, 3478–3482 (2000).
Hohlbaum, A. M., Gregory, M. S., Ju, S. T. & Marshak-Rothstein, A. Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J. Immunol. 167, 6217–6224 (2001).
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).
Sneller, M. C. et al. Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89, 1341–1348 (1997).
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).
Fisher, G. H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995).
Van Parijs, L., Refaeli, Y., Abbas, A. K. & Baltimore, D. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Immunity 11, 763–770 (1999).
Wang, J. et al. Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP. Eur. J. Immunol. 30, 155–163 (2000).
Hennino, A., Berard, M., Casamayor-Palleja, M., Krammer, P. H. & Defrance, T. Regulation of the Fas death pathway by FLICE-inhibitory protein in primary human B cells. J. Immunol. 165, 3023–3030 (2000).
Hennino, A., Berard, M., Krammer, P. H. & Defrance, T. FLICE-inhibitory protein is a key regulator of germinal center B cell apoptosis. J. Exp. Med. 193, 447–458 (2001).
Pellegrini, M. et al. FADD and caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells. Blood 106, 1581–1589 (2005).
Desbarats, J. & Newell, M. K. Fas engagement accelerates liver regeneration after partial hepatectomy. Nature Med. 6, 920–923 (2000).
French, L. E. & Tschopp, J. Inhibition of death receptor signalling by FLICE-inhibitory protein as a mechanism for immune escape of tumours. J. Exp. Med. 190, 891–894 (1999). References 109–112 provide a description of the upregulation of cFLIP in certain tumours.
Djerbi, M. et al. The inhibitor of death receptor signalling, FLICE-inhibitory protein defines a new class of tumour progression factors. J. Exp. Med. 190, 1025–1032 (1999).
Medema, J. P., de Jong, J., van Hall, T., Melief, C. J. & Offringa, R. Immune escape of tumours in vivo by expression of cellular FLICE-inhibitory protein. J. Exp. Med. 190, 1033–1038 (1999).
Ugurel, S. et al. Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-γ. Int. J. Cancer 82, 727–736 (1999).
Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).
Conlon, P., Oksenberg, J. R., Zhang, J. & Steinman, L. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol. Dis. 6, 149–166 (1999).
Catrina, A. I., Ulfgren, A. K., Lindblad, S., Grondal, L. & Klareskog, L. Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann. Rheum. Dis. 61, 934–936 (2002).
Bai, S. et al. NF-κB-regulated expression of cellular FLIP protects rheumatoid arthritis synovial fibroblasts from tumour necrosis factor α-mediated apoptosis. Arthritis Rheum. 50, 3844–3855 (2004).
Moon, R. T., Kohn, A. D., De Ferrari, G. V. & Kaykas, A. WNT and β-catenin signalling: diseases and therapies. Nature Rev. Genet. 5, 691–701 (2004).
Naito, M. et al. Cellular FLIP inhibits β-catenin ubiquitylation and enhances Wnt signalling. Mol. Cell. Biol. 24, 8418–8427 (2004).
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).
This work was supported by funding from the National Institutes of Health, the Swiss National Science Foundation, the National Cancer Institute of Canada, and the Canadian Institutes of Health Research.
The authors declare no competing financial interests.
- Death domain
A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.
- Death-effector domain
(DED). A domain that is found in certain initiator caspases (for example, mammalian caspase-8) and their adaptor protein (for example, FAS-associated via death domain (FADD)). This domain mediates protein–protein interactions.
- Gln-Ala-Cys-X-Gly motif
A cysteine-containing sequence that is found at the enzymatic site of caspases.
- His-Gly motif
A crucial histidine sequence at the enzymatic site that is conserved in caspases.
- Death-inducing signalling complex
(DISC). This complex forms after death-receptor ligation. In the case of CD95, the DISC rapidly recruits FAS-associated via death domain (FADD) through the mutual death-effector domains of CD95 and FADD, followed by caspase-8 and/or cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) recruitment by death-effector domains.
- 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.
- Complementation of Rag1−/− blastocysts
A method for generating lymphocytes deficient in molecules whose absence is lethal in mice. Blastocysts from a gene-knockout mouse are fused with those from Rag1−/− mice. Because Rag1−/− cells cannot give rise to lymphocytes (as their antigen-receptor genes cannot rearrange), lymphocytes that develop from these fusions will occur only from the gene-knockout cells.
An inhibitor of protein kinase C and certain G-protein-coupled receptor kinases.
An inhibitor of protein synthesis.
- Autoimmune lymphoproliferative syndrome
(ALPS). A systemic lupus erythematosus (SLE)-like condition that is seen in patients bearing mutations in CD95.
- BH3-only family
Members of the B-cell lymphoma (BCL-2) family that contain only the BCL-2 homology domain 3 (BH3). BH3-only members are pro-apoptotic.
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Budd, R., Yeh, WC. & Tschopp, J. cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6, 196–204 (2006). https://doi.org/10.1038/nri1787
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