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Endogenous Inhibitors of Caspases

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Abstract

Caspases are cysteine proteases that are specific for aspastic acid residues. These enzymes have been extensively characterized as integral and highly conserved components of a variety of cell death programs. Cowpox and several insect viruses have evolved mechanisms that counter host cell suicide by encoding proteins that directly inhibit caspases—thereby allowing propagation of viral progeny within the host cell. It has only recently been elucidated, however, that endogenous cellular inhibitors of the caspases exist. To date five members of the inhibitor of apoptosis (IAP) family of proteins has been identified in humans and at least three of these have been shown directly to inhibit specific caspases. Thus, members of the IAP family of proteins are the only endogenous inhibitors of caspases known in mammals. Here we discuss the caspase and IAP families of proteins and review the data concerning their relationship.

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REFERENCES

  1. Samali A, Zhivotovsky B, Jones D, Nagata S, Orrenius S: Apoptosis: Cell death defined by caspase activation. Cell Death Different 6:495–496, 1999

    Google Scholar 

  2. Yuan JY, Horvitz HR: The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol 138:33–41, 1990

    Google Scholar 

  3. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR: The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75:641–652, 1993

    Google Scholar 

  4. Miura M, Zhu H, Rotello R, Hartwieg EA, 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 75:653–660, 1993

    Google Scholar 

  5. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J: Human ICE/CED-3 protease nomenclature. Cell 87:171, 1996

    Google Scholar 

  6. Salvesen GS, Dixit VM: Caspases: intracellular signaling by proteolysis. Cell 91:443–446, 1997

    Google Scholar 

  7. Cohen GM: Caspases: The executioners of apoptosis. Biochem J 326:1–16, 1997

    Google Scholar 

  8. Thornberry NA, Lazebnik Y: Caspases: Enemies within. Science 281:1312–1316, 1998

    Google Scholar 

  9. Humke EW, Ni J, Dixit VM: ERICE, A novel FLICE activatable caspase. J Biol Chem 273:15702–15707, 1998

    Google Scholar 

  10. Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS-S, Flavell RA: Altered cytokine export and apoptosis in mice deficient in interleukin-1b converting enzyme. Science 267:2000–2003, 1995

    Google Scholar 

  11. Reed JC: Caspases and cytokines: Roles in inflammation and autoimmunity. Adv Immunol 73:265–287, 1999

    Google Scholar 

  12. Kuida K, Zheng TS, Na S, Kuan C-y, Yang D, Karasuyama H, Rakic P, Flavell RA: Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384:368–372, 1996

    Google Scholar 

  13. Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA: Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337, 1998

    Google Scholar 

  14. Varfolomeev EE, 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 9:267–276, 1998

    Google Scholar 

  15. Bergeron L, Yuan J: Sealing one's fate: Control of cell death in neurons. Curr Opin Neurobiol 8:55–63, 1998

    Google Scholar 

  16. Jiang ZH, Zhang WJ, Rao Y, Wu JY: Regulation of lch-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors. Proc Natl Acad Sci USA 95:9155–9160, 1998

    Google Scholar 

  17. Rothe M, Pan M-G, Henzel WJ, Ayres TM, Goeddel DV: The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243–1252, 1995

    Google Scholar 

  18. 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 15:2685–2689, 1996

    Google Scholar 

  19. Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda J, MacKenzie A, Korneluk RG: Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379:349–353, 1996

    Google Scholar 

  20. Ambrosini G, Adida C, Altieri D: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921, 1997

    Google Scholar 

  21. Hauser HP, Bardroff M, Pyrowolakis G, Jentsch S: A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. J Cell Biol 141:1415–1422, 1998

    Google Scholar 

  22. Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-Linked IAP is a direct inhibitor of cell death proteases. Nature 388:300–303, 1997

    Google Scholar 

  23. Roy N, Deveraux QL, Takashashi R, Salvesen GS, Reed JC: The c-IAP-1 and c-IaP-2 proteins are direct inhibitors of specific caspases. Embo J 16:6914–6925, 1997

    Google Scholar 

  24. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula M, 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 17:2215–2223, 1998

    Google Scholar 

  25. Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen G, Reed J: A single BIR domain of XIAP sufficient for inhibiting caspases. JBC 273:7787–7790, 1998

    Google Scholar 

  26. Deveraux QL, Reed JC: IAP-family of proteins—Supressors of cell death. Genes Dev 13:239–252, 1999

    Google Scholar 

  27. Tamm I, Want Y. Sausville E, Sudiero DA, Vigna N, Oltersdorf T, Reed J: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas(CD95), Bax, and anticancer drugs. Cancer Res 59:5315–5320, 1998

    Google Scholar 

  28. Kobayashi K, Hatano M, Otaki M, Ogasawara T, Tokuhisa T: Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci USA 96:1457–1462, 1999

    Google Scholar 

  29. Kaiser WJ, Vucic D, Miller LK: The Drosophila inhibitor of apoptosis D-IAPI suppresses cell death induced by the caspase drICE. FEBS Lett 440:243–248, 1998

    Google Scholar 

  30. Crook NE, Clem RJ, Miller LK: An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67:2168–2174, 1993

    Google Scholar 

  31. Clem RJ, Miller LK: Control of programmed cell death by the baculovirus genes p35 and iap. Mol Cell Biol 14:5212–5222, 1994

    Google Scholar 

  32. Birnbaum MJ, Clem RJ, Miller LK: An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs. J Virol 68:2521–2528, 1994

    Google Scholar 

  33. Lenarcic B, Turk V: Thyroglobulin type-1 domains in equistatin inhibit both papain-like cysteine proteinases and cathepsin D. J Biol Chem 274:563–566, 1999

    Google Scholar 

  34. Deveraux QL, Leo E, Stennicke H, Welsh K, Salvesen GS, Reed JC: Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J 18:5242–5251, 1999

    Google Scholar 

  35. Hinds MG, Norton RS, Vaux DL, Day CL: Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol 6:648–651, 1999

    Google Scholar 

  36. Stennicke HR, Salvesen GS: Properties of the caspases. Biochim Biophys Acta 1387:17–31, 1998

    Google Scholar 

  37. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X: Apaf-1, a human protein homologous to C. elegans CED-4, particpates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413, 1997

    Google Scholar 

  38. Li P, Nijhawan D, Budihardjo I, Srinivasula S, Ahmad M, Alnemri E, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489, 1997

    Google Scholar 

  39. Reed JC: Cytochrome C: Can't live with it; Can't live without it. Cell 91:559–562, 1997

    Google Scholar 

  40. Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ: Movement of bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292, 1997

    Google Scholar 

  41. Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC: Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 95:4997–5002, 1998

    Google Scholar 

  42. Mahajan N, Linder K, Berry G, Gordon G, Heinm R, Herman B: Bcl-2 and Bax interactions in individual mitochondria probed with mutant green fluorescent proteins and fluorescence resonance energy transfer. Nature Biotechnol 16:547–552, 1998

    Google Scholar 

  43. Bossy-Wetzel E, Newmeyer DD, Green DR: Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49, 1998

    Google Scholar 

  44. Finucane DM, Bossy-Wetzel E, Cotter TG, Green DR: Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-XL. J Biol Chem (in press)

  45. Orth K, Dixit VM: Bik and Bak induce apoptosis downstream of CrmA but upstream of inhibitor of apoptosis. J Biol Chem 272:8841–8844, 1997

    Google Scholar 

  46. Duckett CS, Li F, Tomaselli KJ, Thompson CB, Armstrong RC: Human IAP-like protein regulates programmed cell death downstream of Bcl-XL and cytochrome c. Mol Cell Biol 18:608–615, 1998

    Google Scholar 

  47. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnson A, Lefebvre C, Kang X, Salih M, Aubry H, Tamai K, Guan X, Ioannou P, Crawford TO, de Jong PJ, Surh L, Ikeda J-E, Korneluk RG, MacKenzie A: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167–178, 1995

    Google Scholar 

  48. Liu Q, Fischer U, Wang F, Dreyfuss G: The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90:1013–1021, 1997

    Google Scholar 

  49. Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y: Synergistic anti-apoptotic activity between bcl-2 and smn implicated in spinal muscular atrophy. Nature 390:413–417, 1997

    Google Scholar 

  50. Xu DG, Crocker SJ, Doucet JP, St-Jean M, Tamai K, Hakim AM, Ikeda JE, Liston P, Thompson CS, Korneluk RG, MacKenzie A, Robertson GS: Elevation of neuronal expression of NAIP reduces ischemic damage in the rathippocampus. Nat Med 3:997–1004, 1997

    Google Scholar 

  51. Simons M, Beinroth S, Gleichmann M, Liston P, Korneluk RG, MacKenzie AE, Bahr M, Klockgether T, Robertson GS, Weller M, Schultz JB: Adevovirus-mediated gene transfer of inhibitors of apoptosis proteins delays apoptosis in cerebellar granule neurons. Neurochemistry 72:292–301, 1999

    Google Scholar 

  52. Wagenknecht B, Glaser T, Naumann U, Kugler S, Isenmann S, Bahr M, Korneluk R, Liston P, Weller M: Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma. Cell Death Different 6:370–376, 1999

    Google Scholar 

  53. You M, Ku PT, Hrdlickova R, Bose J: ch-IAPl, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-rel oncoprotein. Mol Cell Biol 17:7328–7341, 1997

    Google Scholar 

  54. Ambrosini G, Adida C, Sirugo G, Altieri DC: Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. 273:11177–11182, 1998

    Google Scholar 

  55. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396:580–584, 1998

    Google Scholar 

  56. Singh A, Ni J, Aggarwal BB: Death domain receptors and their role in cell demise. Interferon Cytokine Res 18:439–540, 1998

    Google Scholar 

  57. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW: Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kB control. Proc Natl Acad Sci USA 94:10057–10062, 1997

    Google Scholar 

  58. Stehlik C, Martin RD, Kumabashiri I, Binder BR, Lipp J: NF-kB regulated x-chromosome-linked IAP gene expression protects endothelial cells from TNF-a induced apoptosis. J Exp Med 188:211–216, 1998

    Google Scholar 

  59. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS: NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683, 1998

    Google Scholar 

  60. McCarthy JV, Dixit VM: Apoptosis induced by Drosophila reaper and grim in a human system. Attenuation by inhibitor of apoptosis proteins (cIAPs). J Biol Chem 273:24009–24015, 1998

    Google Scholar 

  61. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K: XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 18:179–187, 1999

    Google Scholar 

  62. Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM: Yama/CPP32beta, a mammalian homolog of CED-3, is a crmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 81:801–809, 1995

    Google Scholar 

  63. Bump NJ, Hackett M, Hugunin M, Seshagiri S, Brady K, Chen P, Ferenz C, Mankovich J, Shi L, Greenberg AH, Miller LK, Wong WW: Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. Science 269:1885–1888, 1995

    Google Scholar 

  64. Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, Salvesen GS: Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 37:10757–10765, 1998

    Google Scholar 

  65. Fisher AJ, Cruz WD, Zoog SJ, Schneider CL, Friesen PD: Crystal structure of baculovirus P35: Role of a novel reactive site loop in apoptotic caspase inhibition. EMBO 18:2031–2039, 1999

    Google Scholar 

  66. Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM, Salvesen GS: Target protease specificity of the viral serpin CrmA: Analysis of five caspases. J Biol Chem 272:7797–7800, 1997

    Google Scholar 

  67. Sun J, Ooms L, Bird CH, Sutton VR, Trapani JA, Bird PI: A new family of 10 murine ovalbumin serpins includes two homologs of proteinase inhibitor 8 and two homologs of the granzyme B inhibitor (proteinase inhibitor 9). J Biol Chem 272:15434–15441, 1997

    Google Scholar 

  68. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer J-L, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J: Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521, 1997

    Google Scholar 

  69. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J-L, Schröter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J: Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195, 1997

    Google Scholar 

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Deveraux, Q.L., Stennicke, H.R., Salvesen, G.S. et al. Endogenous Inhibitors of Caspases. J Clin Immunol 19, 388–398 (1999). https://doi.org/10.1023/A:1020502800208

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