, Volume 7, Issue 4, pp 313–319 | Cite as

Initiator caspases in apoptosis signaling pathways

  • M. Chen
  • J. Wang


Death receptor- or mitochondrion-dependent apoptosis is initiated by the recruitment and activation of apical caspases in the apoptosis signaling pathways. In death receptor-mediated apoptosis, engagement of death receptors leads to the formation of the death-inducing signaling complex (DISC) containing the death receptors, adaptor proteins, caspase-8 and caspase-10. In mitochondrion-dependent apoptosis, release of cytochrome C into the cytosol results in the formation of apoptosome containing cytochrome C, Apaf-1 and caspase-9. Caspase-8, caspase-10 and caspase-9 are believed to be the initiator caspases at the top of the caspase signaling cascade. Recruitment of caspases to DISC and apoptosome leads to their activation by dimer formation. Recent biochemical and structural analyses of components in the DISC and apoptosome shed new lights on their roles in inducing the onset of apoptosis signaling.

caspase-10 crystal structures death receptors isoforms mitochondrion procaspase processing 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Locksley RM, Killeen N, Lenardo MJ The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 2001; 104: 487-501.Google Scholar
  2. 2.
    Ashkenazi A, Dixit VM Death receptors: Signaling and modulation. Science 1998; 281: 1305-1308.Google Scholar
  3. 3.
    Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, 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 1995; 270: 7795-7798.Google Scholar
  4. 4.
    Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995; 81: 505-512.Google Scholar
  5. 5.
    Kischkel FC, Hellbardt S, Behrmann I, et al Cytotoxicitydependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo J 1995; 14: 5579-5588.Google Scholar
  6. 6.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNFreceptor-induced cell death. Cell 1996; 85: 803-815.Google Scholar
  7. 7.
    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.Google Scholar
  8. 8.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405-413.Google Scholar
  9. 9.
    Li P, Nijhawan D, Budihardjo I, et al Cytochrome c and dATPdependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479-489.Google Scholar
  10. 10.
    Wang X The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15: 2922-2933.Google Scholar
  11. 11.
    Susin SA, Lorenzo HK, Zamzami N, et al Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441-446.Google Scholar
  12. 12.
    Daugas E, Nochy D, Ravagnan L, et al Apoptosis-inducing factor (AIF): A ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 2000; 476: 118-123.Google Scholar
  13. 13.
    Li H, Zhu H, Xu CJ, Yuan J Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491-501.Google Scholar
  14. 14.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94: 481-490.Google Scholar
  15. 15.
    Nakagawa T, Yuan J Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 2000; 150: 887-894.Google Scholar
  16. 16.
    Nakagawa T, Zhu H, Morishima N, et al Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403: 98-103.Google Scholar
  17. 17.
    Fernandes-Alnemri T, Armstrong RC, Krebs J, et al In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci USA 1996; 93: 7464-7469.Google Scholar
  18. 18.
    Vincenz C, Dixit VM Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/ Ced-3 homologue, is proximally involved in CD95-and p55-mediated death signaling. J Biol Chem 1997; 272: 6578-6583.Google Scholar
  19. 19.
    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.Google Scholar
  20. 20.
    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 1998; 8: 1001-1008.Google Scholar
  21. 21.
    Sprick MR, Weigand MA, Rieser E, et al FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 2000; 12: 599-609.Google Scholar
  22. 22.
    Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000; 12: 611-620.Google Scholar
  23. 23.
    Bodmer JL, Holler N, Reynard S, et al TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2000; 2: 241-243.Google Scholar
  24. 24.
    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 2001; 98: 13884-13888.Google Scholar
  25. 25.
    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.Google Scholar
  26. 26.
    Zou H, Li Y, Liu X, Wang X An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274: 11549-11556.Google Scholar
  27. 27.
    Chou JJ, Matsuo H, Duan H, Wagner G Solution structure of the RAIDDCARDand model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 1998; 94: 171-180.Google Scholar
  28. 28.
    Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 2002; in press.Google Scholar
  29. 29.
    Bergeron L, Perez GI, Macdonald G, et al Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 1998; 12: 1304-1314.Google Scholar
  30. 30.
    Thome M, Hofmann K, Burns K, et al Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol 1998; 8: 885-888.Google Scholar
  31. 31.
    Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM ICEBERG: A novel inhibitor of interleukin-1beta generation. Cell 2000; 103: 99-111.Google Scholar
  32. 32.
    Kuida K, Lippke JA, Ku G, et al Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995; 267: 2000-2003.Google Scholar
  33. 33.
    Li P, Allen H, Banerjee S, et al Mice deficient in IL-1 betaconverting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995; 80: 401-411.Google Scholar
  34. 34.
    Jiang D, Zheng L, Lenardo MJ Caspases in T-cell receptorinduced thymocyte apoptosis. Cell Death Differ 1999; 6: 402-411.Google Scholar
  35. 35.
    Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 1996; 384: 638-641.Google Scholar
  36. 36.
    Berglund H, Olerenshaw D, Sankar A, Federwisch M, McDonald NQ, Driscoll PC The three-dimensional solution structure and dynamic properties of the human FADD death domain. J Mol Biol 2000; 302: 171-188.Google Scholar
  37. 37.
    Telliez JB, Xu GY, Woronicz JD, et al Mutational analysis and NMR studies of the death domain of the tumor necrosis factor receptor-1. J Mol Biol 2000; 300: 1323-1333.Google Scholar
  38. 38.
    Sukits SF, Lin LL, Hsu S, Malakian K, Powers R, Xu GY Solution structure of the tumor necrosis factor receptor-1 death domain. J Mol Biol 2001; 310: 895-906.Google Scholar
  39. 39.
    Eberstadt M, Huang B, Chen Z, et al NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 1998; 392: 941-945.Google Scholar
  40. 40.
    Vaughn DE, Rodriguez J, Lazebnik Y, Joshua-Tor L Crystal structure of Apaf-1 caspase recruitment domain: An alphahelical Greek key fold for apoptotic signaling. J Mol Biol 1999; 293: 439-447.Google Scholar
  41. 41.
    Zhou P, Chou J, Olea RS, Yuan J, Wagner G Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: A structural basis for specific adaptor/caspase interaction. Proc Natl Acad Sci USA 1999; 96: 11265-11270.Google Scholar
  42. 42.
    Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1998; 1: 949-957.Google Scholar
  43. 43.
    Yang X, Chang HY, Baltimore D Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1998; 1: 319-325.Google Scholar
  44. 44.
    MacCorkle RA, Freeman KW, Spencer DM Synthetic activation of caspases: Artificial death switches. Proc Natl Acad Sci USA 1998; 95: 3655-3660.Google Scholar
  45. 45.
    Salvesen GS, Dixit VM Caspase activation: The inducedproximity model. Proc Natl Acad Sci USA 1999; 96: 10964-10967.Google Scholar
  46. 46.
    Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW Three-dimensional structure of the apoptosome. Implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002; 9: 423-432.Google Scholar
  47. 47.
    Walker NP, Talanian RV, Brady KD, et al Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: A (p20/p10)2 homodimer. Cell 1994; 78: 343-352.Google Scholar
  48. 48.
    Rotonda J, Nicholson DW, Fazil KM, et al The threedimensional structure of apopain/CPP32, a key mediator of apoptosis. Nat Struct Biol 1996; 3: 619-625.Google Scholar
  49. 49.
    Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y Crystal structure of a procaspase-7 zymogen: Mechanisms of activation and substrate binding. Cell 2001; 107: 399-407.Google Scholar
  50. 50.
    Riedl SJ, Fuentes-Prior P, Renatus M, et al Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci USA 2001; 98: 14790-14795.Google Scholar
  51. 51.
    Renatus M, Stennicke HR, Scott FL, Liddington RC, Salvesen GS Dimer formation drives the activation of the cell death protease caspase 9. Proc Natl Acad Sci USA 2001; 98: 14250-14255.Google Scholar
  52. 52.
    Thornberry NA, Lazebnik Y Caspases: Enemies within. Science 1998; 281: 1312-1316.Google Scholar
  53. 53.
    Zheng L, Trageser CL, Willerford DM, Lenardo MJ T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. J Immunol 1998; 160: 763-769.Google Scholar
  54. 54.
    Schattner EJ, Elkon KB, Yoo DH, et al CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway. J Exp Med 1995; 182: 1557-1565.Google Scholar
  55. 55.
    Wang J, Lenardo MJ Essential lymphocyte function associated 1 (LFA-1): Intercellular adhesion molecule interactions for T cell-mediated B cell apoptosis by Fas/APO-1/CD95. J Exp Med 1997; 186: 1171-1176.Google Scholar
  56. 56.
    Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK Biochemical mechanisms of IL-2-regulated Fas-mediatedTcell apoptosis. Immunity 1998; 8: 615-623.Google Scholar
  57. 57.
    Wang J, Lobito AA, Shen F, Hornung F, Winoto A, Lenardo MJ Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP. Eur J Immunol 2000; 30: 155-163.Google Scholar
  58. 58.
    Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell 1999; 3: 159-167.Google Scholar
  59. 59.
    Srinivasula SM, Hegde R, Saleh A, et al A conserved XIAPinteraction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001; 410: 112-116.Google Scholar
  60. 60.
    Du C, Fang M, Li Y, Li L, Wang X Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33-42.Google Scholar
  61. 61.
    Verhagen AM, Ekert PG, Pakusch M, et al Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102: 43-53.Google Scholar
  62. 62.
    Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 2001; 8: 613-621.Google Scholar
  63. 63.
    Martins LM, Iaccarino I, Tenev T, et al The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277: 439-444.Google Scholar
  64. 64.
    van Loo G, van Gurp M, Depuydt B, et al The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 2002; 9: 20-26.Google Scholar
  65. 65.
    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 2001; 104: 781-790.Google Scholar
  66. 66.
    Wu G, Chai J, Suber TL, et al Structural basis of IAP recognition by Smac/DIABLO. Nature 2000; 408: 1008-1012.Google Scholar
  67. 67.
    Hegde R, Srinivasula SM, Zhang Z, et al Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277: 432-438.Google Scholar
  68. 68.
    Peter ME, Kischkel FC, Scheuerpflug CG, Medema JP, Debatin KM, Krammer PH Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 deathinducing signaling complex. Eur J Immunol 1997; 27: 1207-1212.Google Scholar
  69. 69.
    Teitz T, Wei T, Valentine MB, et al Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000; 6: 529-535.Google Scholar
  70. 70.
    Ng PW, Porter AG, Janicke RU Molecular cloning and characterization of two novel pro-apoptotic isoforms of caspase-10. J Biol Chem 1999; 274: 10301-10308.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • M. Chen
    • 1
  • J. Wang
    • 1
  1. 1.Department of ImmunologyBaylor College of MedicineHoustonUSA

Personalised recommendations