Abstract
Fas is a member of the tumor necrosis factor receptor family that can induce apoptosis by the recruitment and activation of caspase-8 (formerly called FLICE, MACH or MCH-5). Recently, caspase-8/FLICE inhibitory proteins (FLIPs) have been identified as proteins that counteract the caspase-8-dependent apoptosis-promoting activity of Fas and other death receptors. Viral and cellular FLIPs, which share structural similarity with caspase-8, are recruited to the death receptors upon ligand binding and inhibit caspase-8 activation. Viral FLIP family members are present in several lymphotropic herpesviruses and in a human poxvirus, and expression of viral FLIP proteins is thought to prevent or delay the elimination of virus-infected cells by cytotoxic T cells. Cellular FLIP has a similar anti-apoptotic function, but genetic studies have revealed additional, previously unanticipated roles in T-cell proliferation and heart development. Moreover, abnormal expression of cellular FLIP may play a role in autoimmune diseases, in tumor development and in cardiovascular disorders.
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References
Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 2003; 10:26–35.
Boldin MP, Varfolomeev EE, Pancer Z et al. A novel protein that interacts with the death domain of Fas/APOl contains a sequence motif related to the death domain. J Biol Chem 1995; 270:7795–7798.
Chinnaiyan AM, O’Rourke K, Tewari M et al. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995; 81:505–512.
Boldin MP, Goncharov TM, Goltsev YV et al. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 1996; 85:803–815.
Muzio M, Chinnaiyan AM, Kischkel FC 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 1996; 85:817–827.
Kischkel FC, Lawrence DA, Tinel A et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 2001; 276:46639–46646.
Wang J, Chun HJ, Wong W et al. Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 2001; 98:13884–13888.
Sprick MR, Rieser E, Stahl H 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 2002; 21:4520–4530.
Medema JP, Scaffidi C, Kischkel FC et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). Embo J 1997; 16:2794–2804.
Yang X, Chang HY, Baltimore D. Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1998; 1:319–325.
Martin DA, Siegel RM, Zheng L et al. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalphal) death signal. J Biol Chem 1998; 273:4345–4349.
Muzio M, Stockwell BR, Stennicke HR et al. An induced proximity model for caspase-8 activation. J Biol Chem 1998; 273:2926–2930.
Hu S, Vincenz C, Buller M et al. A novel family of viral death effector domain-containing molecules that inhibit both CD-95-and tumor necrosis factor receptor-1-induced apoptosis. J Biol Chem 1997; 272:9621–9624.
Bertin J, Armstrong RC, Ottilie S et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas-and TNFRl-induced apoptosis. Proc Natl Acad Sci USA 1997; 94:1172–1176.
Thome M, Schneider P, Hofmann K et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386:517–521.
Searles RP, Bergquam EP, Axthelm MK et al. Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8. J Virol 1999; 73:3040–3053.
Irmler M, Thome M, Hahne M et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388:190–195.
Shu HB, Halpin DR, Goeddel DV. Casper is a FADD-and caspase-related inducer of apoptosis. Immunity 1997; 6:751–763.
Srinivasula SM, Ahmad M, Ottilie S et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFRl-induced apoptosis. J Biol Chem 1997; 272:18542–18545.
Inohara N, Koseki T, Hu Y et al. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci USA 1997; 94:10717–10722.
Goltsev YV, Kovalenko AV, Arnold E et al. CASH, a novel caspase homologue with death effector domains. J Biol Chem 1997; 272:19641–19644.
Han DK, Chaudhary PM, Wright ME et al. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc Natl Acad Sci USA 1997; 94:11333–11338.
Hu S, Vincenz C, Ni J et al. I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1-and CD-95-induced apoptosis. J Biol Chem 1997; 272:17255–17257.
Rasper DM, Vaillancourt JP, Hadano S 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 1998; 5:271–288.
Cohen GM. Caspases: The executioners of apoptosis. Biochem J 1997; 326 (Pt 1):1–16.
Scaffidi C, Schmitz I, Krammer PH et al. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 1999; 274:1541–1548.
Thome M, Tschopp J. Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol. 2001; 1:50–58.
Krueger A, Schmitz I, Baumann S et al. c-FLIP splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex (DISC). J Biol Chem 2001; 5:5.
Micheau O, Thome M, Schneider P et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem. 2002; 277:45162–45171.
Kataoka T, Budd RC, Holler N et al. The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 2000; 10:640–648.
Micheau O, Lens S, Gaide O et al. NF-kB signals induce the expression of c-FLIP. Molecular and Cellular Biology 2001; 21:5299–5305.
Chang DW, Xing Z, Pan Y et al. c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. Embo J 2002; 21:3704–3714.
Holler N, Zaru R, Micheau O et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunology 2000; 1:489–495.
Chan FK, Shisler J, Bixby JG et al. A role for tumor necrosis factor receptor 2 (TNFR-2) and receptor-interacting protein (RIP) in programmed necrosis and anti-viral responses. J Biol Chem 2003; 278:51613–51621.
Siegel RM, Chan FK, Chun HJ et al. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 2000; 1:469–474.
Krammer PH. CD95’s deadly mission in the immune system. Nature 2000; 407:789–795.
Rieux-Laucat F, Le Deist F, Fischer A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differ 2003; 10:124–133.
Yeh WC, Itie A, Elia AJ et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 2000; 12:633–642.
Yeh WC, Pompa JL, McCurrach ME et al. FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998; 279:1954–1958.
Zhang J, Cado D, Chen A et al. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mortl. Nature 1998; 392:296–300.
Varfolomeev EE, Schuchmann M, Luria V et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity 1998; 9:267–276.
Yeh WC, Hakem R, Woo M et al. Gene targeting in the analysis of mammalian apoptosis and TNF receptor superfamily signaling. Immunol Rev 1999; 169:283–302.
Lens SM, Kataoka T, Former KA et al. The caspase 8 inhibitor c-FLIP(L) modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes. Mol Cell Biol. 2002; 22:5419–5433.
Tai TS, Fang LW, Lai MZ. c-FLICE inhibitory protein expression inhibits T-cell activation. Cell Death Differ 2004; 11:69–79.
Van Parijs L, Refaeli Y, Abbas AK et al. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Immunity 1999; 11:763–770.
Walsh CM, Wen BG, Chinnaiyan AM et al. A role for FADD in T cell activation and development. Immunity 1998; 8:439–449.
Newton K, Harris AW, Bath ML et al. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. Embo J 1998; 17:706–718.
Newton K, Kurts C, Harris AW et al. Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells. Curr Biol 2001; 11:273–276.
Salmena L, Lemmers B, Hakem A et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 2003; 17:883–895.
Chun HJ, Zheng L, Ahmad M et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 2002; 419:395–399.
Zornig M, Hueber AO, Evan G. p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice. Curr Biol 1998; 8:467–470.
Newton K, Harris AW, Strasser A. FADD/MORT1 regulates the preTCR checkpoint and can function as a tumour suppressor. Embo J 2000; 19:931–941.
Algeciras-Schimnich A, Griffith TS, Lynch DH et al. Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis. J Immunol 1999; 162:5205–5211.
Kirchhoff S, Muller W, Krueger A et al. TCR-Mediated Up-Regulation of c-FLIP(short) Correlates with Resistance Toward CD95-Mediated Apoptosis by Blocking Death-Inducing Signaling Complex Activity. J Immunol 2000; 165:6293–6300.
Inaba M, Kurasawa K, Mamura M et al. Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells. J Immunol 1999; 163:1315–1320.
Kiener PA, Davis PM, Starling GC et al. Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages. J Exp Med 1997; 185:1511–1516.
Perlman H, Pagliari LJ, Georganas C et al. FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis. J Exp Med 1999; 190:1679–1688.
Willems F, Amraoui Z, Vanderheyde N et al. Expression of c-FLIP(L) and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: Inhibition by bisindolylmaleimide. Blood 2000; 95:3478–3482.
Rescigno M, Piguet V, Valzasina B et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J Exp Med 2000; 192:1661–1668.
Micheau O. Cellular FLICE-inhibitory protein: An attractive therapeutic target? Expert Opin Ther Targets 2003; 7:559–573.
Semra YK, Seidi OA, Sharief MK. Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis. J Neuroimmunol 2001; 113:268–274.
Sharief MK. Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis [In Process Citation]. J Neuroimmunol 2000; 111:203–209.
Conlon P, Oksenberg JR, Zhang J et al. The immunobiology of multiple sclerosis: An autoimmune disease of the central nervous system. Neurobiol Dis 1999; 6:149–166.
Perlman H, Pagliari LJ, Liu H et al. Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein and are refractory to Fas-mediated apoptosis. Arthritis Rheum 2001; 44:21–30.
Stassi G, Di Liberto D, Todaro M et al. Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. Nature Immunology 2000; 1:483–488.
Imanishi T, Murry CE, Reinecke H et al. Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues. Cardiovasc Res 2000; 48:101–110.
Steenbergen C, Afshari CA, Petranka JG et al. Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure. Am J Physiol Heart Circ Physiol Jan 2003; 284:H268–276.
Imanishi T, McBride J, Ho Q et al. Expression of cellular FLICE-inhibitory protein in human coronary arteries and in a rat vascular injury model. Am J Pathol 2000; 156:125–137.
Sata M, Walsh K. Endothelial cell apoptosis induced by oxidized LDL is associated with the down-regulation of the cellular caspase inhibitor FLIP. J Biol Chem 1998; 273:33103–33106.
Djerbi M, Screpanti V, Catrina AI et al. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med 1999; 190:1025–1032.
Medema JP, de Jong J, van Hall T et al. Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 1999; 190:1033–1038.
Screpanti V, Wallin RP, Ljunggren HG et al. A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. J Immunol 2001; 167:2068–2073.
Taylor MA, Chaudhary PM, Klem J et al. Inhibition of the death receptor pathway by cFLIP confers partial engraftment of MHC class I-deficient stem cells and reduces tumor clearance in perforin-deficient mice. J Immunol 2001; 167:4230–4237.
Ryu BK, Lee MG, Chi SG et al. Increased expression of cFLIP(L) in colonic adenocarcinoma. J Pathol 2001; 194:15–19.
Thomas RK, Kallenborn A, Wickenhauser C et al. Constitutive expression of c-FLIP in Hodgkin and Reed-Sternberg cells. Am J Pathol 2002; 160:1521–1528.
Hueber AO, Zornig M, Bernard AM et al. 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 2000; 275:10453–10462.
Wang J, Zheng L, Lobito A et al. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 1999; 98:47–58.
Perlman H, Liu H, Georganas C et al. Differential expression pattern of the antiapoptotic proteins, Bcl-2 and FLIP, in experimental arthritis. Arthritis Rheum 2001; 44:2899–2908.
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Thome, M. (2006). Regulation of Fas Signaling by FLIP Proteins. In: Fas Signaling. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-34573-6_4
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DOI: https://doi.org/10.1007/0-387-34573-6_4
Publisher Name: Springer, Boston, MA
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