Abstract
Receptors belonging to the tumor necrosis factor receptor family have long been thought to play an important role in the regulation of immunity. Although this family is composed of a large number of surface receptors that potentiate myriad functions in vivo, a subset is known to directly convey apoptotic signals. One such molecule belonging to this subset is CD95. Ligation of CD95 instigates the formation of a complex known as the “death-inducing signaling complex” or DISC, which is composed of molecules including FADD (Fas associated with death domain) and RIP (receptor-interacting kinase), as well as procaspases-8 and -10, and a caspase-8-like molecule that lacks proteolytic activity called c-FLIP. Although the DISC was initially thought to serve an exclusively proapoptotic role, humans and mice with defects in various components of this complex demonstrate a variety of developmental and hematopoietic defects that are not apparently due to aberrant apoptosis. These findings paint a far more complex picture of the numerous components of the DISC, and provide evidence that these complexes serve nonapoptotic functions. Herein, we summarize the experimental evidence challenging the notion that the DISC imparts an exclusively apoptotic function and provide hypotheses to account for these alternative roles. Rather than operating as a binary system, we propose that the DISCs formed around various DRs transduce signals leading to a variety of cellular fates.
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Kischkel F, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer P, Peter M: Cytotoxicity-dependent APO-1 Fas/CD95-associated proteins form a death-inducing signaling complex DISC with the receptor. EMBO J 14: 5579, 1995
Nagata S, Golstein P: The Fas death factor. Science 267: 1449, 1995
Rieux-Laucat F, Le Deist F, Fischer A: Autoimmune lymphoproliferative syndromes: Genetic defects of apoptosis pathways. Cell Death Differ 10: 124, 2003
Lenardo MJ: Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis Nature 353: 858, 1991
Kabelitz D, Pohl T, Pechhold K: Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today 14: 338, 1993
Brunner T, Mogil R, LaFace D, Yoo N, Mahboubi A, Echeverri F, Martin S, Force W, Lynch D, Ware C, et al.: Cell-autonomous Fas CD95 /Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature:373: 441, 1995
Dhein J, Walczak H, Baumler C, Debatin K, Krammer P: Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373: 438, 1995
Ju S, Panka D, Cui H, Ettinger R, el-Khatib M, Sherr D, Stanger B, Marshak-Rothstein A: Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373: 444, 1995
Allen R, Marshall J, Roths J, Sidman C: Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules. J Exp Med:172: 1367, 1990
Matsuzawa A, Moriyama T, Kaneko T, Tanaka M, Kimura M, Ikeda H, Katagiri T: A new allele of the lpr locus, lprcg, that complements the gld gene in induction of lymphadenopathy in the mouse. J Exp Med:171: 519, 1990
Watanabe-Fukunaga R, Brannan C, Copeland N, Jenkins N, Nagata S: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature:356: 314, 1992
Takahashi T, Tanaka M, Brannan C, Jenkins N, Copeland N, Suda T, Nagata S: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell:76: 969, 1994
Lynch D, Watson M, Alderson M, Baum P, Miller R, Tough T, Gibson M, Davis-Smith T, Smith C, Hunter K, et al.: The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity:1: 131, 1994
Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM: Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81: 935, 1995
Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB: Fas gene mutations in the Canale—Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 335: 1643, 1996
Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP: Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268: 1347, 1995
Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, Notarangelo LD: Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: A molecular and immunological analysis. Blood 89:902, 1997
Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, Fleisher TA, Lim MS, Jaffe ES, Puck JM, Lenardo MJ, Straus SE: Clincial, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89: 1341, 1997
Dianzani U, Chiocchetti A, Ramenghi U: Role of inherited defects decreasing Fas function in autoimmunity. Life Sci 72: 2803, 2003
Dianzani U, Bragardo M, DiFranco D, Alliaudi C, Scagni P, Buonfiglio D, Redoglia V, Bonissoni S, Correra A, Dianzani I, Ramenghi U: Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Blood 89: 2871, 1997
Kisielow P, Bluthmann H, Staerz U, Steinmetz M, von Boehmer H: Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature:333: 742, 1988
Hogquist K, Jameson S, Bevan M: Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. Immunity:3: 79, 1995
Surh C, Sprent J: T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature:372: 100, 1994
Clayton L, Ghendler Y, Mizoguchi E, Patch R, Ocain T, Orth K, Bhan A, Dixit V, Reinherz E: T-cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: The molecular basis of negative selection. EMBO J:16: 2282, 1997
Viret C, Janeway CA, Jr: MHC and T cell development. Rev Immunogenet 1:91, 1999
Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T cells. Annu Rev Immunol 21: 139, 2003
Shi Y, Bissonnette R, Parfrey N, Szalay M, Kubo R, Green D: In vivo administration of monoclonal antibodies to the CD3 T cell receptor complex induces cell death (apoptosis) in immature thymocytes. J Immunol:146: 3340, 1991
Castro J, Listman J, Jacobson B, Wang Y, Lopez P, Ju JS, Finn P, Perkins D: Fas modulation of apoptosis during negative selection of thymocytes. Immunity:5: 617, 1996
Zhou T, Bluethmann H, Eldridge J, Brockhaus M, Berry K, Mountz J: Abnormal thymocyte development and production of autoreactive T cells in T cell receptor transgenic autoimmune mice. J Immunol:147: 466, 1991
Singer G, Abbas A: The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity:1: 365, 1994
Cornall RJ, Goodnow CC, Cyster JG: The regulation of self-reactive B cells. Curr Opin Immunol 7: 804, 1995
Walsh C, Wen B, Chinnaiyan A, O'Rourke K, Dixit V, Hedrick S: A role for FADD in T cell activation and development. Immunity:8(4):439, 1998
Newton K, Harris A, Bath M, Smith K, Strasser A: A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J:17(3):706, 1998
Zornig M, Hueber A, Evan G: p53-Dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice. Curr Biol:8(8):467, 1998
Zhang J, Cado D, Chen A, Kabra N, Winoto A: Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature:392: 296, 1998
Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW: FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279: 1954, 1998
Kerr J, Wyllie A, Currie A: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer:26: 239, 1972
Ferguson E, Horvitz H: Identification and characterization of 22 genes that affect the vulval cell lineages of the nematode Caenorhabditis elegans. Genetics:110(1):17, 1985
Ferguson E, Sternberg P, Horvitz H: A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature:326: 259, 1987
Hengartner M, Horvitz H: Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev:4(4):581, 1994
Ellis HM, Horvitz HR: Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817, 1986
Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, et al.: Molecular cloning of the interleukin-1 beta converting enzyme. Science 256: 97, 1992
Miura M, Zhu H, Rotello R, Hartwieg E, Yuan J: Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell:75(4):653, 1993
Thornberry NA, Lazebnik Y: Caspases: Enemies within. Science 281: 1312, 1998
Alnemri E, Livingston D, Nicholson D, Salvesen G, Thornberry N, Wong W, Yuan J: Human ICE/CED-3 protease nomenclature [Letter]. Cell:87: 171, 1996
Kolb WP, Granger GA: Lymphocyte in vitro cytotoxicity: Characterization of human lymphotoxin. Proc Natl Acad Sci USA 61: 1250, 1968
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72: 3666, 1975
Ware CF, Granger GA: Mechanisms of lymphocyte-mediated cytotoxicity. III: Characterization of the mechanism of inhibition of the human alloimmune lymphocyte-mediated cytotoxic reaction by polyspecific anti-lymphotoxin sera in vitro. J Immunol 126: 1934, 1981
Ware CF, Granger GA: Mechanisms of lymphocyte-mediated cytotoxicity. I: The effects of anti-human lymphotoxin antisera on the cytolysis of allogeneic B cell lines by MLC-sensitized human lymphocytes in vitro. J Immunol 126: 1919, 1981
Ware CF, Harris PC, Granger GA: Mechanisms of lymphocyte-mediated cytotoxicity. II: Biochemical and serologic identification of a precursor lymphotoxin form (pre-LT) produced by MLC-sensitized human T lymphocytes in vitro. J Immunol 126: 1927, 1981
Clark WR, Walsh CM, Glass AA, Hayashi F, Matloubian M, Ahmed R: Molecular pathways of CTL-mediated cytotoxicity. Immunol Rev 146: 33, 1995
Gupta S: A decision between life and death during TNF-alpha-induced signaling. J Clin Immunol 22: 185, 2002
Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med 169: 1747, 1989
Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, Debatin KM, Krammer PH: Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301, 1989
Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233, 1991
Suda T, Takahashi T, Golstein P, Nagata S: Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell:75(6):1169, 1993
Rathmell J, Townsend S, Xu J, Flavell R, Goodnow C: Expansion or elimination of B cells in vivo: Dual roles for CD40-and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell:87(2):319, 1996
Rathmell JC, Fournier S, Weintraub BC, Allison JP, Goodnow CC: Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4(+) T cells. J Exp Med 188: 651, 1998
Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75: 253, 1993
Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, Schmits R, Simard JJ, Ohashi PS, Griesser H, et al.: Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268: 1472, 1995
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3: 521, 1995
Van Parijs L, Biuckians A, Ibragimov A, Alt FW, Willerford DM, Abbas AK: Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor. J Immunol 158: 3738, 1997
Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK: Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8: 615, 1998
Spaner D, Raju K, Rabinovich B, Miller RG: A role for perforin in activation-induced T cell death in vivo: Increased expansion of allogeneic perforin-deficient T cells in SCID mice. J Immunol 162: 1192, 1999
Hildeman DA, Mitchell T, Teague TK, Henson P, Day BJ, Kappler J, Marrack PC: Reactive oxygen species regulate activation-induced T cell apoptosis. Immunity 10: 735, 1999
Mitchell TC, Hildeman D, Kedl RM, Teague TK, Schaefer BC, White J, Zhu Y, Kappler J, Marrack P: Immunological adjuvants promote activated T cell survival via induction of Bcl-3. Nat Immunol 2: 397, 2001
Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J, Marrack P: Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 16: 759, 2002
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J: Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1: 489, 2000
Malek TR, Yu A, Vincek V, Scibelli P, Kong L: CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17: 167, 2002
Malek TR, Yu A, Scibelli P, Lichtenheld MG, Codias EK: Broad programming by IL-2 receptor signaling for extended growth to multiple cytokines and functional maturation of antigen-activated T cells. J Immunol 166: 1675, 2001
Zheng L, Fisher G, Miller R, Peschon J, Lynch D, Lenardo M: Induction of apoptosis in mature T cells by tumour necrosis factor. Nature:377: 348, 1995
Sytwu H, Liblau R, McDevitt H: The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity:5(1):17, 1996
Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, Peschon J, Chen YH: Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/-mice. Nat Immunol 4: 255, 2003
LeBlanc HN, Ashkenazi A: Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10: 66, 2003
Smith K, Strasser A, Vaux D: CrmA expression in T lymphocytes of transgenic mice inhibits CD95 Fas/APO-1-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J:15: 5167, 1996
Song K, Chen Y, Goke R, Wilmen A, Seidel C, Goke A, Hilliard B: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 191: 1095, 2000
Wang EC, Thern A, Denzel A, Kitson J, Farrow SN, Owen MJ: DR3 regulates negative selection during thymocyte development. Mol Cell Biol 21: 3451, 2001
Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P: TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16: 479, 2002
Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM: Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J Exp Med 194:1441, 2001
Schmidt CS, Liu J, Zhang T, Song HY, Sandusky G, Mintze K, Benschop RJ, Glasebrook A, Yang DD, Na S: Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6. J Exp Med 197: 51, 2003
Itoh N, Nagata S: A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268: 10932, 1993
Ashkenazi A, Dixit VM: Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11: 255, 1999
Chinnaiyan A, O'Rourke K, Tewari M, Dixit V: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell:81: 505, 1995
Boldin M, Varfolomeev E, Pancer Z, Mett I, Camonis J, Wallach D: A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem:270(14):7795, 1995
Chinnaiyan A, Tepper C, Seldin M, O'Rourke K, Kischkel F, Hellbardt S, Krammer P, Peter M, Dixit V: FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem:271(9):4961, 1996
Muzio M, Chinnaiyan A, Kischkel F, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz J, Zhang M, Gentz R, Mann M, Krammer P, Peter M, Dixit V: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell:85(6):817, 1996
Boldin M, Goncharov T, Goltsev Y, Wallach D: Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell:85(6):803, 1996
Medema J, Scaffidi C, Kischkel F, Shevchenko A, Mann M, Krammer P, Peter M: FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J:16(10):2794, 1997
Salvesen GS, Dixit VM: Caspase activation: The induced-proximity model. Proc Natl Acad Sci USA 96: 10964, 1999
Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM: An induced proximity model for caspase-8 activation. J Biol Chem 273: 2926, 1998
MacCorkle RA, Freeman KW, Spencer DM: Synthetic activation of caspases: Artificial death switches. Proc Natl Acad Sci USA 95: 3655, 1998
Stennicke HR, Jurgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D, Green DR, Reed JC, Froelich CJ, Salvesen GS: Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 273: 27084, 1998
Hu S, Vincenz C, Ni J, Gentz R, Dixit VM: I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1-and CD-95-induced apoptosis. J Biol Chem 272: 17255, 1997
Ng PW, Porter AG, Janicke RU: Molecular cloning and characterization of two novel proapoptotic isoforms of caspase-10. J Biol Chem 274: 10301, 1999
Kischkel FC, Lawrence DA, Tinel A, LeBlanc H, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D, Ashkenazi A: Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 276: 46639, 2001
Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ: Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 98: 13884, 2001
Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H: Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but cannot functionally substitute caspase-8. Embo J 21: 4520, 2002
Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ: Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98: 47, 1999
Stanger B, Leder P, Lee T, Kim E, Seed B: RIP: A novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell:81(4):513, 1995
Ting AT, Pimentel-Muinos FX, Seed B: RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. EMBO J 15: 6189, 1996
Kelliher M, Grimm S, Ishida Y, Kuo F, Stanger B, Leder P: The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity:8(3):297, 1998
Beg A, Baltimore D: An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science:274: 782, 1996
Van Antwerp D, Martin S, Kafri T, Green D, Verma I: Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science:274(5288)
Cusson N, Oikemus S, Kilpatrick ED, Cunningham L, Kelliher M: The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death. J Exp Med 196: 15, 2002
Hsu H, Xiong J, Goeddel D: The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell:81(4):495, 1995
Hsu H, Shu H, Pan M, Goeddel D: TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell:84(2)
Baud V, Karin M: Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11: 372, 2001
Thome M, Tschopp J: Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol 1: 50, 2001
Ahmad M, Srinivasula SM, Wang L, Talanian RV, Litwack G, Fernandes-Alnemri T, Alnemri ES: CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer Res 57: 615, 1997
Duan H, Dixit VM: RAIDD is a new “death” adaptor molecule. Nature 385: 86, 1997
Hofmann K, Bucher P, Tschopp J: The CARD domain: A new apoptotic signalling motif. Trends Biochem Sci 22: 155, 1997
Chou JJ, Matsuo H, Duan H, Wagner G: Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 94: 171, 1998
Peter ME, Krammer PH: The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 10: 26, 2003
Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K, Ramsdell F, Lynch DH: Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178: 2231, 1993
Kennedy NJ, Kataoka T, Tschopp J, Budd RC: Caspase activation is required for T cell proliferation. J Exp Med 190: 1891, 1999
Zhang J, Winoto A: A mouse Fas-associated protein with homology to the human Mort1/FADD protein is essential for Fas-induced apoptosis. Mol Cell Biol:16: 2756, 1996
Juo P, Kuo CJ, Yuan J, Blenis J: Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol 8: 1001, 1998
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D: 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, 1998
Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J, Tschopp J: TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2: 241, 2000
Newton K, Kurts C, Harris AW, Strasser A: Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells. Curr Biol 11: 273, 2001
Beisner DR, Chu IH, Arechiga AF, Hedrick SM, Walsh CM: The requirements for FADD signaling in mature T cell activation and survival. J Immunol:171: 247, 2003
Zhang J, Kabra NH, Cado D, Kang C, Winoto A: FADD-deficient T cells exhibit a disaccord in regulation of the cell cycle machinery. J Biol Chem 276: 29815, 2001
Hueber AO, Zornig M, Bernard AM, 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, 2000
Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ: Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419: 395, 2002
Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PY, Berry DM, Tamblyn L, Shehabeldin A, Migon E, Wakeham A, Bouchard D, Yeh WC, McGlade JC, Ohashi PS, Hakem R: Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 17: 883, 2003
Alam A, Cohen LY, Aouad S, Sekaly RP: Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med 190: 1879, 1999
Newton K, Harris AW, Strasser A: FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. Embo J 19: 931, 2000
Kabra NH, Kang C, Hsing LC, Zhang J, Winoto A: T cell-specific FADD-deficient mice: FADD is required for early T cell development. Proc Natl Acad Sci USA 98: 6307, 2001
Groettrup M, von Boehmer H: A role for a pre-T-cell receptor in T-cell development. Immunol Today:14(12):610, 1993
Green DR: The suicide in the thymus, a twisted trail. Nat Immunol 4: 207, 2003
Scaffidi C, Kischkel FC, Krammer PH, Peter ME: Analysis of the CD95 (APO-1/Fas) death-inducing signaling complex by high-resolution two-dimensional gel electrophoresis. Methods Enzymol 322: 363, 2000
Scaffidi C, Volkland J, Blomberg I, Hoffmann I, Krammer PH, Peter ME: Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase. J Immunol 164: 1236, 2000
Hua ZC, Sohn SJ, 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, 2003
Kennedy NJ, Budd RC: Phosphorylation of FADD/MORT1 and Fas by kinases that associate with the membrane-proximal cytoplasmic domain of Fas. J Immunol 160: 4881, 1998
Rochat-Steiner V, Becker K, Micheau O, Schneider P, Burns K, Tschopp J: FIST/HIPK3; A Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation. J Exp Med 192: 1165, 2000
Rasper DM, Vaillancourt JP, Hadano S, Houtzager VM, Seiden I, Keen SL, Tawa P, Xanthoudakis S, Nasir J, Martindale D, Koop BF, Peterson EP, Thornberry NA, Huang J, MacPherson DP, Black SC, Hornung F, Lenardo MJ, Hayden MR, Roy S, Nicholson DW: 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, 1998
Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, Mirtsos C, Suzuki N, Bonnard M, Goeddel DV, Mak TW: Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12:633, 2000
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J, Schroter M, Burns K, Mattmann C, Rimoldi D, French L, Tschopp J: Inhibition of death receptor signals by cellular FLIP. Nature:388: 190, 1997
Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM, Hood L: MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc Natl Acad Sci USA 94: 11333, 1997
Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S: Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem 276:20633, 2001
Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grutter MG: The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem 277: 45162, 2002
Krueger A, Baumann S, Krammer PH, Kirchhoff S: FLICE-inhibitory proteins: Regulators of death receptor-mediated apoptosis. Mol Cell Biol 21: 8247, 2001
Scaffidi C, Schmitz I, Krammer PH, Peter ME: The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274: 1541, 1999
Algeciras-Schimnich A, Griffith TS, Lynch DH, Paya CV: Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis. J Immunol 162:5205, 1999
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J: The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10: 640, 2000
Dong C, Davis RJ, Flavell RA: MAP kinases in the immune response. Annu Rev Immunol 20: 55, 2002
Van Parijs L, Refaeli Y, Abbas AK, Baltimore D: Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Immunity 11: 763, 1999
Lens SM, Kataoka T, Fortner KA, Tinel A, Ferrero I, MacDonald RH, Hahne M, Beermann F, Attinger A, Orbea HA, Budd RC, Tschopp J: 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, 2002
Algeciras-Schimnich A, Barnhart BC, Peter ME: Apoptosis-independent functions of killer caspases. Curr Opin Cell Biol 14: 721, 2002
Deveraux QL, Schendel SL, Reed JC: Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families. Cardiol Clin 19: 57, 2001
added. Deveraux QL, Reed JC: IAP family proteins—Suppressors of apoptosis. Genes Dev 13: 239, 1999
Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al.: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80: 167, 1995
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV: The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83: 1243, 1995
Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB: A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. Embo J 15:2685, 1996
Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3: 917, 1997
Deveraux QL, Reed JC: IAP family proteins—Suppressors of apoptosis. Genes Dev 13: 239, 1999
Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300, 1997
Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC: IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. Embo J 17: 2215, 1998
Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB: Characterization of XIAP-deficient mice. Mol Cell Biol 21: 3604, 2001
Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H: Structural basis of caspase inhibition by XIAP: Differential roles of the linker versus the BIR domain. Cell 104:781, 2001
Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y, Dataa P: Structural basis of caspase-7 inhibition by XIAP. Cell 104: 769, 2001
Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS: Structural basis for the inhibition of caspase-3 by XIAP. Cell 104: 791, 2001
Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL: The antiapoptotic activity of XIAP is retained upon mutation of both the caspase 3-and caspase 9-interacting sites. J Cell Biol 157: 115, 2002
Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD: Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288: 874, 2000
Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD: Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288:874, 2000
Suzuki Y, Nakabayashi Y, Takahashi R: Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its antia-poptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 98: 8662, 2001
Denecker G, Vercammen D, Declercq W, Vandenabeele P: Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 58: 356, 2001
Wilson CA, Browning JL: Death of HT29 adenocarcinoma cells induced by TNF family receptor activation is caspase-independent and displays features of both apoptosis and necrosis. Cell Death Differ 9: 1321, 2002
Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P: Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 187: 1477, 1998
Liu CY, Takemasa A, Liles WC, Goodman RB, Jonas M, Rosen H, Chi E, Winn RK, Harlan JM, Chuang PI: Broad-spectrum caspase inhibition paradoxically augments cell death in TNF-alpha-stimulated neutrophils. Blood 101:295, 2003
Luschen S, Ussat S, Scherer G, Kabelitz D, Adam-Klages S: Sensitization to death receptor cytotoxicity by inhibition of fas-associated death domain protein (FADD)/caspase signaling. Requirement of cell cycle progression. J Biol Chem 275: 24670, 2000
Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S: Caspase-independent cell killing by Fas-associated protein with death domain. J Cell Biol 143:1353, 1998
Ruemmele FM, Dionne S, Levy E, Seidman EG: TNFalpha-induced IEC-6 cell apoptosis requires activation of ICE caspases whereas complete inhibition of the caspase cascade leads to necrotic cell death. Biochem Biophys Res Commun 260: 159, 1999
Luhrs KA: Manuscript in preparation
DiDonato J, Hayakawa M, Rothwarf D, Zandi E, Karin M: A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature:388: 548, 1997
Hsu H, Huang J, Shu H, Baichwal V, Goeddel D: TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity:4: 387, 1996
Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM: Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem 277:9505, 2002
Lin Y, Devin A, Rodriguez Y, Liu ZG: Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 13: 2514, 1999
Slee EA, Adrain C, Martin SJ: Executioner caspase-3,-6, and-7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 276: 7320, 2001
Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P: Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol 4:387, 2003
Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W: Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 267: 5317, 1992
Goossens V, Stange G, Moens K, Pipeleers D, Grooten J: Regulation of tumor necrosis factor-induced, mitochondria-and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I. Antioxid Redox Signal 1: 285, 1999
Cande C, Cecconi F, Dessen P, Kroemer G: Apoptosis-inducing factor (AIF): Key to the conserved caspase-independent pathways of cell death? J Cell Sci 115: 4727, 2002
Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A, Herceg Z, Wang ZQ, Schulze-Osthoff K: Activation and caspase-mediated inhibition of PARP: A molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol Biol Cell 13: 978, 2002
Arnoult D, Parone P, Martinou JC, Antonsson B, Estaquier J, Ameisen JC: Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. J Cell Biol 159: 923, 2002
Du L, Zhang X, Han YY, Burke NA, Kochanek PM, Watkins SC, Graham SH, Carcillo JA, Szabo C, Clark RS: Intra-mitochondrial poly-ADP-ribosylation contributes to NAD+ depletion and cell death induced by oxidative stress. J Biol Chem 278:18426, 2003
Cande C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, Kroemer G: Apoptosis-inducing factor (AIF): A novel caspase-independent death effector released from mitochondria. Biochimie 84: 215, 2002
Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D, Brothers G, Penninger JM, Peleato ML, Kroemer G, Susin SA: NADH oxidase activity of mitochondrial apoptosis-inducing factor. J Biol Chem 276:16391, 2001
Hirt UA, Gantner F, Leist M: Phagocytosis of nonapoptotic cells dying by caspase-independent mechanisms. J Immunol 164: 6520, 2000
Ono K, Wang X, Han J: Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency. Mol Cell Biol 21: 8276, 2001
Ono K, Kim SO, Han J: Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death. Mol Cell Biol 23: 665, 2003
Kim JW, Choi EJ, Joe CO: Activation of death-inducing signaling complex (DISC) by proapoptotic C-terminal fragment of RIP. Oncogene 19: 4491, 2000
Doerfler P, Forbush KA, Perlmutter RM: Caspase enzyme activity is not essential for apoptosis during thymocyte development. J Immunol 164: 4071, 2000
Gett AV, Hodgkin PD: A cellular calculus for signal integration by T cells. Nat Immunol 1: 239, 2000
van Stipdonk MJ, Lemmens EE, Schoenberger SP: Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol 2: 423, 2001
Kaech SM, Ahmed R: Memory CD8+ T cell differentiation: Initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2: 415, 2001
Wong P, Pamer EG: Cutting edge: Antigen-independent CD8 T cell proliferation. J Immunol 166:5864, 2001
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Walsh, C.M., Luhrs, K.A. & Arechiga, A.F. The “Fuzzy Logic” of the Death-Inducing Signaling Complex in Lymphocytes. J Clin Immunol 23, 333–353 (2003). https://doi.org/10.1023/A:1025313415487
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DOI: https://doi.org/10.1023/A:1025313415487