Abstract
Death effector domains (DEDs) are protein interaction modules found in a number of proteins known to regulate apoptosis from death receptors. The core DED family members that orchestrate programmed cell death from death receptors include the adaptor protein FADD, the initiator caspases procaspases-8 and -10 and the regulatory protein c-FLIP. Through homotypic DED interactions, these proteins assemble into the death-inducing signaling complex (DISC) to regulate initiator caspase activation and launch the apoptotic proteolytic cascade. A considerable body of evidence, however, is revealing that the same core group of DED-containing proteins also paradoxically promotes survival and proliferation in lymphocytes and possibly other cell types. This review delves into recent findings regarding these two opposing functional aspects of the core DED proteins. We discuss the current effort expanding our structural and biochemical view of how DED proteins assemble into the DISC to fully activate initiator caspases and execute cell death, and finally we examine details linking the same proteins to proliferation and describe how this outcome might be achieved through restricted activation of initiator caspases.
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References
Abe K, Kurakin A, Mohseni-Maybodi M, Kay B, Khosravi-Far R . (2000). The complexity of TNF-related apoptosis-inducing ligand. Ann NY Acad Sci 926: 52–63.
Alappat EC, Feig C, Boyerinas B, Volkland J, Samuels M, Murmann AE et al. (2005). Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities. Mol Cell 19: 321–332.
Alcivar A, Hu S, Tang J, Yang X . (2003). DEDD and DEDD2 associate with caspase-8/10 and signal cell death. Oncogene 22: 291–297.
Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K et al. (1993). Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178: 2231–2235.
Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME . (2002). Molecular ordering of the initial signaling events of CD95. Mol Cell Biol 22: 207–220.
Ashkenazi A, Dixit VM . (1998). Death receptors: signaling and modulation. Science 281: 1305–1308.
Bagneris C, Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C et al. (2008). Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell 30: 620–631.
Bang S, Jeong EJ, Kim IK, Jung YK, Kim KS . (2000). Fas- and tumor necrosis factor-mediated apoptosis uses the same binding surface of FADD to trigger signal transduction. A typical model for convergent signal transduction. J Biol Chem 275: 36217–36222.
Bao Q, Shi Y . (2007). Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14: 56–65.
Beisner DR, Ch'en IL, Kolla RV, Hoffmann A, Hedrick SM . (2005). Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J Immunol 175: 3469–3473.
Berglund H, Olerenshaw D, Sankar A, Federwisch M, McDonald NQ, Driscoll PC . (2000). The three-dimensional solution structure and dynamic properties of the human FADD death domain. J Mol Biol 302: 171–188.
Bidere N, Snow AL, Sakai K, Zheng L, Lenardo MJ . (2006). Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-kappaB activation. Curr Biol 16: 1666–1671.
Boatright KM, Deis C, Denault JB, Sutherlin DP, Salvesen GS . (2004). Activation of caspases-8 and -10 by FLIP(L). Biochem J 382: 651–657.
Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM et al. (2003). A unified model for apical caspase activation. Mol Cell 11: 529–541.
Boissonnas A, Bonduelle O, Lucas B, Debre P, Autran B, Combadiere B . (2002). Differential requirement of caspases during naive T cell proliferation. Eur J Immunol 32: 3007–3015.
Carrington PE, Sandu C, Wei Y, Hill JM, Morisawa G, Huang T et al. (2006). The structure of FADD and its mode of interaction with procaspase-8. Mol Cell 22: 599–610.
Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ . (2000). A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288: 2351–2354.
Chang DW, Xing Z, Capacio VL, Peter ME, Yang X . (2003). Interdimer processing mechanism of procaspase-8 activation. EMBO J 22: 4132–4142.
Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S et al. (2002). c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J 21: 3704–3714.
Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K et al. (2006). The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124: 601–613.
Chau H, Wong V, Chen NJ, Huang HL, Lin WJ, Mirtsos C et al. (2005). Cellular FLICE-inhibitory protein is required for T cell survival and cycling. J Exp Med 202: 405–413.
Chaudhary PM, Jasmin A, Eby MT, Hood L . (1999). Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18: 5738–5746.
Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM et al. (2002). Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419: 395–399.
Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalo P, Oriente F et al. (1999). PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 18: 4409–4415.
Curtin JF, Cotter TG . (2003). Live and let die: regulatory mechanisms in Fas-mediated apoptosis. Cell Signal 15: 983–992.
Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.
Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK . (2003). Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5: 118–125.
Desbarats J, Newell MK . (2000). Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6: 920–923.
Dohrman A, Kataoka T, Cuenin S, Russell JQ, Tschopp J, Budd RC . (2005). Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-kappa B activation. J Immunol 174: 5270–5278.
Donepudi M, Mac Sweeney A, Briand C, Grutter MG . (2003). Insights into the regulatory mechanism for caspase-8 activation. Mol Cell 11: 543–549.
Eberstadt M, Huang B, Chen Z, Meadows RP, Ng SC, Zheng L et al. (1998). NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 392: 941–945.
Field N, Low W, Daniels M, Howell S, Daviet L, Boshoff C et al. (2003). KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci 116: 3721–3728.
Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN . (2005). c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem 280: 14507–14513.
Golks A, Brenner D, Krammer PH, Lavrik IN . (2006). The c-FLIP-NH2 terminus (p22-FLIP) induces NF-kappaB activation. J Exp Med 203: 1295–1305.
Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D . (1997). CASH, a novel caspase homologue with death effector domains. J Biol Chem 272: 19641–19644.
Green DR, Evan GI . (2002). A matter of life and death. Cancer Cell 1: 19–30.
Guasparri I, Wu H, Cesarman E . (2006). The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO Rep 7: 114–119.
Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT et al. (1997). 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.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Hill JM, Morisawa G, Kim T, Huang T, Wei Y, Werner MH . (2004). Identification of an expanded binding surface on the FADD death domain responsible for interaction with CD95/Fas. J Biol Chem 279: 1474–1481.
Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F et al. (2003). Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol 23: 1428–1440.
Hu S, Vincenz C, Ni J, Gentz R, Dixit VM . (1997). I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. J Biol Chem 272: 17255–17257.
Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW . (1996). NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384: 638–641.
Inohara N, Koseki T, Hu Y, Chen S, Nunez G . (1997). CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci USA 94: 10717–10722.
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V et al. (1997). Inhibition of death receptor signals by cellular FLIP. Nature 388: 190–195.
Jeong EJ, Bang S, Lee TH, Park YI, Sim WS, Kim KS . (1999). The solution structure of FADD death domain. Structural basis of death domain interactions of Fas and FADD. J Biol Chem 274: 16337–16342.
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M et al. (2000). The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10: 640–648.
Kataoka T, Tschopp J . (2004). N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway. Mol Cell Biol 24: 2627–2636.
Kaufmann M, Bozic D, Briand C, Bodmer JL, Zerbe O, Kohl A et al. (2002). Identification of a basic surface area of the FADD death effector domain critical for apoptotic signaling. FEBS Lett 527: 250–254.
Kennedy NJ, Kataoka T, Tschopp J, Budd RC . (1999). Caspase activation is required for T cell proliferation. J Exp Med 190: 1891–1896.
Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH et al. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14: 5579–5588.
Krammer PH . (2000). CD95's deadly mission in the immune system. Nature 407: 789–795.
Krueger A, Baumann S, Krammer PH, Kirchhoff S . (2001). FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 21: 8247–8254.
Lee HJ, Pyo JO, Oh Y, Kim HJ, Hong SH, Jeon YJ et al. (2007). AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. Nat Cell Biol 9: 1303–1310.
Lens SM, Kataoka T, Fortner KA, Tinel A, Ferrero I, MacDonald RH et al. (2002). The caspase 8 inhibitor c-FLIP(L) modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes. Mol Cell Biol 22: 5419–5433.
Li FY, Jeffrey PD, Yu JW, Shi Y . (2006). Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling. J Biol Chem 281: 2960–2968.
Li H, Zhu H, Xu CJ, Yuan J . (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.
Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM . (2002). The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem 277: 13745–13751.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.
Maedler K, Fontana A, Ris F, Sergeev P, Toso C, Oberholzer J et al. (2002). FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication. Proc Natl Acad Sci USA 99: 8236–8241.
Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH et al. (1997). FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16: 2794–2804.
Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW et al. (2002). The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem 277: 45162–45171. e-pub ahead of print 4 September 2002.
Misra RS, Russell JQ, Koenig A, Hinshaw-Makepeace JA, Wen R, Wang D et al. (2007). Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation. J Biol Chem 282: 19365–19374.
Mitsiades CS, Poulaki V, Fanourakis G, Sozopoulos E, McMillin D, Wen Z et al. (2006). Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation. Clin Cancer Res 12: 3705–3712.
Muppidi JR, Lobito AA, Ramaswamy M, Yang JK, Wang L, Wu H et al. (2006). Homotypic FADD interactions through a conserved RXDLL motif are required for death receptor-induced apoptosis. Cell Death Differ 13: 1641–1650.
Muppidi JR, Siegel RM . (2004). Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nat Immunol 5: 182–189.
Naito M, Katayama R, Ishioka T, Suga A, Takubo K, Nanjo M et al. (2004). Cellular FLIP inhibits beta-catenin ubiquitylation and enhances Wnt signaling. Mol Cell Biol 24: 8418–8427.
Nakagiri S, Murakami A, Takada S, Akiyama T, Yonehara S . (2005). Viral FLIP enhances Wnt signaling downstream of stabilized beta-catenin, leading to control of cell growth. Mol Cell Biol 25: 9249–9258.
Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh WC, Yagita H et al. (2006). An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J 25: 5549–5559.
Ozoren N, El-Deiry WS . (2003). Cell surface death receptor signaling in normal and cancer cells. Semin Cancer Biol 13: 135–147.
Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK et al. (2007). The CD95 receptor: apoptosis revisited. Cell 129: 447–450.
Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN et al. (2005). Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 280: 20722–20729.
Qi W, Wu H, Yang L, Boyd DD, Wang Z . (2007). A novel function of caspase-8 in the regulation of androgen-receptor-driven gene expression. EMBO J 26: 65–75.
Rasper DM, Vaillancourt JP, Hadano S, Houtzager VM, Seiden I, Keen SL et al. (1998). 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.
Rathmell JC, Thompson CB . (2002). Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109 (Suppl): S97–107.
Rawlings DJ, Sommer K, Moreno-Garcia ME . (2006). The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6: 799–812.
Reed JC, Doctor KS, Godzik A . (2004). The domains of apoptosis: a genomics perspective. Sci STKE 2004: re9.
Renganathan H, Vaidyanathan H, Knapinska A, Ramos JW . (2005). Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J 390: 729–735.
Riedl SJ, Shi Y . (2004). Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5: 897–907.
Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PY et al. (2003). Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 17: 883–895.
Sandu C, Morisawa G, Wegorzewska I, Huang T, Arechiga AF, Hill JM et al. (2006). FADD self-association is required for stable interaction with an activated death receptor. Cell Death Differ 13: 2052–2061.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al. (1998). Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17: 1675–1687.
Scaffidi C, Schmitz I, Krammer PH, Peter ME . (1999). The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274: 1541–1548.
Shu HB, Halpin DR, Goeddel DV . (1997). Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6: 751–763.
Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D et al. (2000). Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288: 2354–2357.
Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, Cohen J et al. (1998). Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141: 1243–1253.
Siegel RM, Muppidi JR, Sarker M, Lobito A, Jen M, Martin D et al. (2004). SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. J Cell Biol 167: 735–744.
Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y et al. (1997). FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J Biol Chem 272: 18542–18545.
Stilo R, Liguoro D, di Jeso B, Leonardi A, Vito P . (2003). The alpha-chain of the nascent polypeptide-associated complex binds to and regulates FADD function. Biochem Biophys Res Commun 303: 1034–1041.
Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA . (2001). Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155: 459–470.
Stupack DG, Teitz T, Potter MD, Mikolon D, Houghton PJ, Kidd VJ et al. (2006). Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439: 95–99.
Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J et al. (2005). Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307: 1465–1468.
Thomas LR, Henson A, Reed JC, Salsbury FR, Thorburn A . (2004). Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD. J Biol Chem 279: 32780–32785.
Thomas LR, Stillman DJ, Thorburn A . (2002). Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen. J Biol Chem 277: 34343–34348.
Thorburn J, Moore F, Rao A, Barclay WW, Thomas LR, Grant KW et al. (2005). Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. Mol Biol Cell 16: 1189–1199.
Vaux DL, Flavell RA . (2000). Apoptosis genes and autoimmunity. Curr Opin Immunol 12: 719–724.
Vilimanovich U, Bumbasirevic V . (2008). TRAIL induces proliferation of human glioma cells by c-FLIPL-mediated activation of ERK1/2. Cell Mol Life Sci 65: 814–826.
Wajant H . (2003). Death receptors. Essays Biochem 39: 53–71.
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. (1999). Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5: 157–163.
Wang S, El-Deiry WS . (2003). TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22: 8628–8633.
Yang JK, Wang L, Zheng L, Wan F, Ahmed M, Lenardo MJ et al. (2005). Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition. Mol Cell 20: 939–949.
Yao Z, Duan S, Hou D, Heese K, Wu M . (2007). Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism. EMBO J 26: 1068–1080.
Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S et al. (2004). Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304: 1500–1502.
Yuan J, Yankner BA . (2000). Apoptosis in the nervous system. Nature 407: 802–809.
Zhang J, Cado D, Chen A, Kabra NH, Winoto A . (1998). Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392: 296–300.
Zhang N, He YW . (2005). An essential role for c-FLIP in the efficient development of mature T lymphocytes. J Exp Med 202: 395–404.
Acknowledgements
Work from Yigong Shi's laboratory in this area of research was supported by a grant from the National Institutes of Health (2 R01 CA90269). Jong W Yu is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-1905-06).
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