Skip to main content

Regulation of Fas Signaling by FLIP Proteins

  • Chapter
  • 322 Accesses

Part of the book series: Medical Intelligence Unit ((MIUN))

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.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 2003; 10:26–35.

    Article  PubMed  CAS  Google Scholar 

  2. 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.

    Article  PubMed  CAS  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. 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.

    Article  PubMed  CAS  Google Scholar 

  10. Yang X, Chang HY, Baltimore D. Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1998; 1:319–325.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. Muzio M, Stockwell BR, Stennicke HR et al. An induced proximity model for caspase-8 activation. J Biol Chem 1998; 273:2926–2930.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. Thome M, Schneider P, Hofmann K et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386:517–521.

    Article  PubMed  CAS  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. Irmler M, Thome M, Hahne M et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388:190–195.

    Article  PubMed  CAS  Google Scholar 

  18. Shu HB, Halpin DR, Goeddel DV. Casper is a FADD-and caspase-related inducer of apoptosis. Immunity 1997; 6:751–763.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Goltsev YV, Kovalenko AV, Arnold E et al. CASH, a novel caspase homologue with death effector domains. J Biol Chem 1997; 272:19641–19644.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. Cohen GM. Caspases: The executioners of apoptosis. Biochem J 1997; 326 (Pt 1):1–16.

    PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Thome M, Tschopp J. Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol. 2001; 1:50–58.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  CAS  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. Krammer PH. CD95’s deadly mission in the immune system. Nature 2000; 407:789–795.

    Article  PubMed  CAS  Google Scholar 

  37. Rieux-Laucat F, Le Deist F, Fischer A. Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death Differ 2003; 10:124–133.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

    Article  PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. Tai TS, Fang LW, Lai MZ. c-FLICE inhibitory protein expression inhibits T-cell activation. Cell Death Differ 2004; 11:69–79.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  Google Scholar 

  46. Walsh CM, Wen BG, Chinnaiyan AM et al. A role for FADD in T cell activation and development. Immunity 1998; 8:439–449.

    Article  PubMed  CAS  Google Scholar 

  47. 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.

    Article  PubMed  CAS  Google Scholar 

  48. 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.

    Article  PubMed  CAS  Google Scholar 

  49. 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.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    PubMed  CAS  Google Scholar 

  54. 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.

    PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. 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.

    Article  PubMed  CAS  Google Scholar 

  57. 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.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    PubMed  CAS  Google Scholar 

  59. 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.

    Article  PubMed  CAS  Google Scholar 

  60. Micheau O. Cellular FLICE-inhibitory protein: An attractive therapeutic target? Expert Opin Ther Targets 2003; 7:559–573.

    Article  PubMed  CAS  Google Scholar 

  61. 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.

    Article  PubMed  CAS  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. 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.

    Article  PubMed  CAS  Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. 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.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. 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.

    Article  PubMed  CAS  Google Scholar 

  70. 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.

    Article  PubMed  CAS  Google Scholar 

  71. 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.

    Article  PubMed  CAS  Google Scholar 

  72. 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.

    PubMed  CAS  Google Scholar 

  73. 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.

    PubMed  CAS  Google Scholar 

  74. Ryu BK, Lee MG, Chi SG et al. Increased expression of cFLIP(L) in colonic adenocarcinoma. J Pathol 2001; 194:15–19.

    Article  PubMed  CAS  Google Scholar 

  75. 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.

    PubMed  CAS  Google Scholar 

  76. 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.

    Article  PubMed  CAS  Google Scholar 

  77. 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.

    Article  PubMed  CAS  Google Scholar 

  78. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

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

Download citation

Publish with us

Policies and ethics