Tissue Transglutaminase: A Candidate Effector Element of Physiological Cell Death

  • M. Piacentini
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 200)


The metazoans possess a genetic program of cell death (defined morphologically as apoptosis) which plays a vital role in their development and maintainance of tissue homeostasis (Wyllie et al. 1980; Fesus et al. 1991b). Over the last few years, it has become clear that cells not only control their proliferative and differentiative pathways, but also need specific positive stimuli to survive (Fesus et al. 1991 b; Raff et al. 1992). In the absence of the appropriate survival signals, cells enter an active program of cell death which requires the participation of functionally distinct sets of genes (Arends and Wyllie 1991; Fesus et al. 1991b). Despite its widespread importance, little is yet known about the biochemical events leading to the physiological deletion of cells in tissues (Arends and Wyllie 1991; Fesus et al. 1991b). While the mechanisms of initiation and regulation of apoptosis have attracted the attention of many researchers, by far less interest has been focused on the effector genes that determine the irreversible phenotypical changes and clearance of the dying cells. These final events allows naturally occurring cell death to behave as a “social” phenomenon which does not produce damage or inflammation in tissues (Arends and Wyllie 1991; Fesus et al. 1991b). Several independent laboratories have shown tissue transglutaminase (tTG) to be a potentially important player in the last stage of the cell death program (for review see Piacentini et al. 1994).


Programme Cell Death Tissue Transglutaminase Effector Element Cell Death Gene Occur Cell Death 
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  1. Aeschlimann D, Wetterwald A, Fleisch H, Paulsson M (1993) Expression of tissue transglutaminase in skeletal tissue correlates with events of terminal differentiation of chondrocytes. J Cell Biol 120: 1461–1470PubMedCrossRefGoogle Scholar
  2. Ameisen JC, Capron A (1991) Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today 4: 102–105Google Scholar
  3. Amendola A, Lombardi L, Oliverio S, Colizzi V, Piacentini M (1994) HIV-I gp120-dependent induction of apoptosis in antigen specific human T cell clones is chracterized by tissue transglutaminase expression and is prevented by cyclosporin A. FEBS Lett 339: 258–264PubMedCrossRefGoogle Scholar
  4. Arends MJ, Wyllie AH (1991) Apoptosis. Mechanism and role in pathology. Int Rev Exp Pathol 32: 223–245PubMedGoogle Scholar
  5. Baldari CT, Macchia G, Heguy A, Melli M, Telford J (1991) Cyclosporin A blocks calcium-dependent pathways of gene activation. J Biol Chem 266: 19103–19108PubMedGoogle Scholar
  6. Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly RP, Finkel TH (1992) Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 176: 1099–1106PubMedCrossRefGoogle Scholar
  7. Bergamini A, Capozzi M, Piacentini M (1994) MCS-F stimulation induces cell death in HIV infected multinucleated monocyte. Immunol Lett 42: 35–40PubMedCrossRefGoogle Scholar
  8. Bursch W, Oberhammer F, Schulte-Hermann R (1992) Cell death by apoptosis and its protective role against disease. TIPS 13: 245–251PubMedGoogle Scholar
  9. Buttyan R, Olsson CA, Pintar J, Chang C, Bandyk M, Poying NG, Sawczuk IS (1989) Induction of TRPM-2 gene in cells undergoing programmed cell death. Mol Cell Biol 9: 3473–3481PubMedGoogle Scholar
  10. Cefai D, Debre P, Kaczorek M, Idziorek T, Autran B, Bismuth G (1990) Human immunodeficiency virus I glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway. J Clin Invest 86: 2117–2124PubMedCrossRefGoogle Scholar
  11. Cohen JJ, Duke RC, Fadok VA, Sellins KS (1992) Apoptosis and programmed cell death in immunity. Annu Rev Immunol 10: 267–293PubMedCrossRefGoogle Scholar
  12. Critchfield JM, Racke MK, Zuniga-Pflucker JC, Cannella B, Raine CS, Goverman J, Lenardo MJ (1994) T cell deletion in high dose therapy of autoimmune encephalomyelitis. Science 263: 1139–1142PubMedCrossRefGoogle Scholar
  13. Diamond D, Sleckman B, Gregory T, Lasky L, Greestain J, Burakoff S (1990) Inhibition of CD4+T-Cell function by the HIV-envelope protein gp120. J Immunol 141: 3715–3717Google Scholar
  14. Dini L, Autuori F, Lentini A, Oliverio S, Piacentini M (1992) The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor. FEBS Lett 296: 174–178PubMedCrossRefGoogle Scholar
  15. Eastman A (1994) Deoxyribonuclease II in apoptosis and the significance of intracellular acidification. Cell Death Differ 1: 7–9PubMedGoogle Scholar
  16. Ellis RE, Yuan J, Horvitz HR (1991) Mechanism and functions of cell death. Annu Rev Cell Biol 7: 663–698PubMedCrossRefGoogle Scholar
  17. Evan, GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69: 119–128PubMedCrossRefGoogle Scholar
  18. Fauci AS (1988) The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 239: 617–622PubMedCrossRefGoogle Scholar
  19. Fesus L, Szucs EF, Barrett KE, Metcalfe DD, Folk JE (1985) Activation of transglutaminase and production of protein-bound γ-glutamylhistamine in stimulated mouse mast cells. J Biol Chem 260: 13771–13778PubMedGoogle Scholar
  20. Fesus L, Thomazy V, Falus A (1987) Induction and activation of tissue transglutaminase during programmed cell death. FEBS Lett 224: 104–108PubMedCrossRefGoogle Scholar
  21. Fesus L, Thomazy V, Autuori F, Ceru MP, Tarcsa E, Piacentini M (1989) Apoptotic hepatocytes become insoluble in detergents and chaotropic agents as a result of transglutaminase action. FEBS Lett 245: 150–154PubMedCrossRefGoogle Scholar
  22. Fesus L, Tarcsa E, Kedei E, Autuori F, Piacentini M (1991 a) Degradation of cells dying by apoptosis leads to accumulation of ε(γ-glutamyl)lysine isodipeptide in culture fluid and blood. FEBS Lett 284: 109–112PubMedCrossRefGoogle Scholar
  23. Fesus L, Davies PJA, Piacentini M (1991b) Apoptosis: molecular mechanism in programmed cellular death. Eur J Cell Biol 56: 170–177PubMedGoogle Scholar
  24. Folk JE (1980) Transglutaminases. Annu Rev Biochem 49: 517–431PubMedCrossRefGoogle Scholar
  25. Folk JE, Finlayson S (1977) The ε(γ-glutamyl)lysine crosslink and the catalytic role of transglutaminase. Adv Prot Chem 31: 1–133CrossRefGoogle Scholar
  26. Gentile V, Saydak M, Chiocca EA, Akande O, Birckbicheler PJ, Lee KN, Stein JP, Davies PJA (1991) Isolation and characterization of cDNA clones to mouse macrophage and human endothelial cell tissue transglutaminases. J Biol Chem 264: 478–483Google Scholar
  27. Gentile V, Thomazy V, Piacentini M, Fesus L, Davies PJA (1992) Expression of tissue transglutaminase in balb-c 3t3 fibroblasts: effects on cellular morphology and adhesion. J Cell Biol 119: 463–474PubMedCrossRefGoogle Scholar
  28. Gougeon ML, Montagnier L (1992) New concepts in the mechanisms of CD4+ lymphocyte depletion in aids, and the influence of opportunistic infections. Res Microbiol 361–373Google Scholar
  29. Green H (1977) Terminal differentiation of cultured human epidermal cells. Cell 11: 405–416PubMedCrossRefGoogle Scholar
  30. Geenberg CS, Birckbichler P, Rice RH (1992) Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 5: 3071–3077Google Scholar
  31. Groux H, Torpier G, Monté D, Mouton Y, Capron A, Ameisen JC (1992) Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med 175: 331–340PubMedCrossRefGoogle Scholar
  32. Hockenbery D, Zutter M, Hickey W, Nahm M, Korsmeyer SJ (1990) Bcl-2 protein is an inner mitochondrial membrane protein that blocks topographically programmed cell death. Nature 348: 334–336PubMedCrossRefGoogle Scholar
  33. Hughes FM, Cidlowski JA (1994) Apoptotic DNA degradation: evidence for novel enzymes. Cell Death Differ 1: 11–17PubMedGoogle Scholar
  34. Ichinose A, Hendrickson LE, Fujikawa K, Davie DJ (1986) Amino acid sequence of the subunit of human factor XIII. Biochemistry 25: 6900–6906PubMedCrossRefGoogle Scholar
  35. Ikura K, Nasu T, Yokota T, Tsuchiya Y, Sasaki R, Chiba H (1988) Amino acid sequence of guinea pig liver transglutaminasi from its cDNA sequence. Biochemistry 27: 2898–2905PubMedCrossRefGoogle Scholar
  36. Kabelitz D, Pohl D, Pechhold K (1993) Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today 14: 338–345PubMedCrossRefGoogle Scholar
  37. Kim IG, Gorman JJ, Park SC, Chung SI, Steinert PM (1993) The deduced sequence of the novel protransglutaminase E (TGase3) of human and mouse. J Biol Chem 268: 12682–12690PubMedGoogle Scholar
  38. Klein JD, Guzman E, Kuehn GD (1992) Purification and partial characterization of transglutaminase from physarum polycephalum. J Bacteriol 174: 2599–2604PubMedGoogle Scholar
  39. Knight CRL, Rees RC, Griffin M (1991) Apoptosis: a potential role for cytosolic transglutaminase and its importance in tumor progression. Biochim Biophys Acta 1096: 312–320PubMedGoogle Scholar
  40. Knight CRL, Hand D, Piacentini M, Griffin M (1993a) Characterization of the transglutaminase mediated large molecular weight polymer from rat liver; its relationship to apoptosis and its importance in carcinogenesis and tumour progression. Eur J Cell Biol 60: 210–217PubMedGoogle Scholar
  41. Knight CRL, Rees RC, Platts A, Johnson T, Griffin M (1993b) Interleukin-2-activated effector lymphocytes mediate cytotoxicity by indicing apoptosis in human leukaemia and solid tumor target cells. Immunology 79: 535–541PubMedGoogle Scholar
  42. Laurent-Crawford AG, Krust B, Muller S, Riviere Y, Rey-Cuillé MA, Bechet JM, Montagnier L, Hovanessien AG (1991) The cytopathic effect of HIV is associated with apoptosis. Virology 185: 829–839PubMedCrossRefGoogle Scholar
  43. Lorand L, Hsu LKH, Siefring GE, Rafferty NS (1981) Lens transglutaminase and cataract formation. Proc Natl Acad Sci USA 78: 1356–1362PubMedCrossRefGoogle Scholar
  44. Mariniello L, Esposito C, Di Pierro P, Cozzolino A, Pucci P, Porta R (1993) HIV transmembrane glycoprotein gp41 is an amino acceptor and donor substrate for transglutaminase in vitro. Eur J Biochem 215: 99–104PubMedCrossRefGoogle Scholar
  45. Mastino A, Piacentini M, Grelli S, Favalli C, Autuori F, Tentori L, Oliverio S, Garaci E (1992) Induction of apoptosis in thymocytes by prostaglandin PE2 in vivo. Dev Immunol 2: 263–271PubMedCrossRefGoogle Scholar
  46. Mastino A, Grelli S, Piacentini M, Oliverio S, Favalli C, Perno F, Garaci E (1993) Correlation between induction of lymphocyte apoptosis and prostaglandin PGE2 production by macrophages infected with HIV. Cell Immunol 152: 120–130PubMedCrossRefGoogle Scholar
  47. McConkey DJ, Orrenius S, Jondal M (1990) Cellular signaling in programmed cell death (apoptosis). Immunol Today 11: 120–121PubMedCrossRefGoogle Scholar
  48. Melino G, Annicchiarico-Petruzzelli M, Piredda P, Candì E, Gentile V, Davies PJA, Piacentini M (1994) “tissue” tansglutaminase and apoptosis: sense and antisense transfection studies in human neuroblastoma cells Mol Cell Biol 14: 6584–6596PubMedGoogle Scholar
  49. Meyaard L, Otto SA, Jonker RR, Mijnster MJ, Keet RPM, Miedema F (1992) programmed death of T cells in HIIV infection. Science 257: 217–219PubMedCrossRefGoogle Scholar
  50. Miura M, Zhu H, Roteilo R, Hartwieg EA, Yuani (1993) Induction of apoptosis in fibroblasts by IL-1B-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75: 653–660PubMedCrossRefGoogle Scholar
  51. Newell MK, Haughn LJ, Maroun CR, Julius MH (1990) Death of mature T cells by separate ligation of CD4 and T cell receptor for antigen. Nature 347: 286–289PubMedCrossRefGoogle Scholar
  52. Novogrodsky A, Quittner S, Rubin L, Stenzel KH (1978) Transglutaminase activity in human lymophocytes: early activation by phytomitogens. Proc Natl Acad Sci USA 75: 1157–1161PubMedCrossRefGoogle Scholar
  53. Palmer DB, Hayday A, Owen MJ (1993) Is TCRbeta expression an essential event in early thymocyte development. Immunol Today 14: 460–462PubMedCrossRefGoogle Scholar
  54. Pantaleo G, Graziosi C, Denmarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotier DP, Fauci AS (1993) HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362: 355–358PubMedCrossRefGoogle Scholar
  55. Peitsch MC, Polzar B, Stephan H, Crompton T, MacDonald HR, Mannherz HG, Tschopp J (1993) Characterization of the endogenous deoxyribonuclease involved in nuclear DNA degradation during apoptosis (programmed cell death). EMBO J 12: 371–377PubMedGoogle Scholar
  56. Piacentini M, Martinet N, Beninati S, Folk JE (1988) Free and protein-conjugated polyamines in mouse epidermal cells. J Biol Chem 263: 3790–3794PubMedGoogle Scholar
  57. Piacentini M, Autuori F, Dini L, Farrace MG, Ghibelli L, Piredda L, Fesus L (1991a) “tissue” transglutaminase is specifically expressed in neonatal rat liver cells undergoing apoptosis upon epidermal growth factor-stimulation. Cell Tissue Res 263: 227–235PubMedCrossRefGoogle Scholar
  58. Piacentini M, Fesus L, Farrace MG, Ghibelli L, Piredda P, Melino G (1991b) The expression of “tissue” transglutaminase in two human cancer cell lines is related with the programmed cell death (apoptosis). Eur J Cell Biol 54: 246–254PubMedGoogle Scholar
  59. Piacentini M, Davies PJA, Fesus L (1994) Transglutaminase in cells undergoing apoptosis. In: Tornei LO, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in desease. Cold Spring Harbor Laboratory press, Cold Spring Harbor, pp 143–163Google Scholar
  60. Raff MC, Barris BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD (1992) Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262: 695–700CrossRefGoogle Scholar
  61. Ritter MA, Boyd RL (1993) Development in the thymus: it takes two to tango. Immunol Today 14: 462–469PubMedCrossRefGoogle Scholar
  62. Savill JS, Dransfield I, Hogg A, Haslett C (1990) Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343: 170–173PubMedCrossRefGoogle Scholar
  63. Shi L, Nishioka WK, Th’ng J, Bradbury EM, Litchfield DW, Grenberg AH (1994) Premature p34cdc2 activation required for apoptosis. Science 263: 1143–1145PubMedCrossRefGoogle Scholar
  64. Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJT (1989) Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 337: 181–184PubMedCrossRefGoogle Scholar
  65. Strange R, Li F, Saurer S, Burkhard A. Friis RR (1992) Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development 115: 49–58PubMedGoogle Scholar
  66. Suto N, Ikura K, Shinagawa R, Sasaki R (1993) Identification of promoter region of guinea pig liver transglutaminase gene. Biochim Biophys Acta 1172: 319–322PubMedGoogle Scholar
  67. Tarcsa E, Kedei N, Thomazy V, Fesus L (1993) An involucrin-like protein in hepatocytes serves as a substrate of tissue transglutaminase during apoptosis. J Biol Chem 267: 25648–25652Google Scholar
  68. Terai C, Korbluth RS, Pauza CD, Richmann DD. Carson DA (1991) Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest 87: 1710–1715PubMedCrossRefGoogle Scholar
  69. Thomazy V, Fesus L (1989) Differential expression of tissue transglutaminase in human cells. Cell Tissue Res 255: 215–224PubMedCrossRefGoogle Scholar
  70. Williams-Ashman HG (1984) Transglutaminases and the clotting of mammalian seminal fluid. Mol Cell Biochem 58: 51–61PubMedCrossRefGoogle Scholar
  71. Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68: 251–306PubMedCrossRefGoogle Scholar
  72. Yonish-Rouach ED, Resnitzky S, Lotem J, Sachs S, Kimichi G, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352: 345–348PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • M. Piacentini
    • 1
  1. 1.Department of BiologyUniversity of Rome “Tor Vergata”RomeItaly

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