Advertisement

Apoptosis

, Volume 12, Issue 3, pp 475–487 | Cite as

The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells

Article

Abstract

Peptidylarginine deiminase IV (PADI4) posttranslationally converts peptidylarginine to citrulline. It plays an essential role in immune cell differentiation and apoptosis. A haplotype of single-nucleotide polymorphisms (SNPs) in PADI4 is functionally relevant as a rheumatoid arthritis (RA) gene. It could increase enzyme activity leading to raised levels of citrullinated protein and stimulating autoantibody. Previously, our study showed that inducible PADI4 causes haematopoietic cell death. Herein, we further investigate whether RA risk PADI4 haplotype (SNP PADI4; S55G, A82V and A112G) and the increase of its enzymatic activity induce apoptosis. In the tetracycline (Tet)-On Jurkat T cells, ionomycin (Ion) only treatment didn't induce apoptosis however it promoted inducible PADI4-decreased cell viability and -enhanced apoptosis. Through in vitro and in vivo PADI enzyme activity assay, we demonstrated that PADI4 enzyme activity of SNP PADI4 was higher than RA non-risk PADI4 haplotype (WT PADI4). The effect of SNP PADI4-induced apoptosis was superior to WT PADI4. In addition, both Ion and SNP PADI4 synergistically provoked apoptosis were compared with both Ion and WT PADI4. Concurrently, in the conditionally inducible SNP PADI4 cells of Ion treatment-induced apoptosis, not only the expression of Bcl-xL was down-regulated and Bax up-regulated, but also cytochrome c was released from mitochondria to cytoplasm in significant amounts. Western blotting data showed the increase in apoptosomal caspase activation during programmed cell death in the inducible SNP PADI4 cells subsequent to Ion treatment. These data demonstrated that both SNP PADI4 increasing their enzyme activity could enhance apoptosis through the mitochondrial pathway and further provide a conceivable explanation in the pathogenesis of RA following the upregulation of PADI4 activity in its SNPs.

Keywords

PADIs SNP PADI4 Apoptosis Bax Bcl-xL Cytochrome c 

Abbreviations

PADIs

Peptidylarginine deiminases

SNP

Single nucleotide polymorphism

Ion

Ionomycin

Notes

Acknowledgments

This study was financially supported by the Chung Shan Medical University grant CSMU 94-OM-A-098, 95-OM-A-103, 95-OM-A-104, and by grants from the National Science Council NSC 93-2745-B-040-005-URD, 94-2745-B-040-008-URD and 95-2745-B-040-009-URD.

References

  1. 1.
    Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25:1106–1118PubMedCrossRefGoogle Scholar
  2. 2.
    Suzuki A, Yamada R, Chang X et al. (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402PubMedCrossRefGoogle Scholar
  3. 3.
    Tommasi C, Petit-Teixeira E, Cournu-Rebeix I et al. (2006) PADI4 gene in multiple sclerosis: a family-based association study. J Neuroimmunol 177:142–145PubMedCrossRefGoogle Scholar
  4. 4.
    Ishida-Yamamoto A, Senshu T, Takahashi H, Akiyama K, Nomura K, Iizuka H (2000) Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis. J Invest Dermatol 114:701–705PubMedCrossRefGoogle Scholar
  5. 5.
    Maruyama N, Ishigami A (2005) Pathophysiological significances of citrullinated proteins in geriatric diseases. Nippon Ronen Igakkai Zasshi 42:519–522PubMedGoogle Scholar
  6. 6.
    Ishigami A, Ohsawa T, Hiratsuka M et al. (2005) Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease. J Neurosci Res 80:120–128PubMedCrossRefGoogle Scholar
  7. 7.
    Guerrin M, Ishigami A, Mechin MC et al. (2003) cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I. Biochem J 370:167–174PubMedCrossRefGoogle Scholar
  8. 8.
    Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N (2002) Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys 407:25–31PubMedCrossRefGoogle Scholar
  9. 9.
    Kanno T, Kawada A, Yamanouchi J et al. (2000) Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol 115:813–823PubMedCrossRefGoogle Scholar
  10. 10.
    Nakashima K, Hagiwara T, Ishigami A et al. (1999) Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem 274:27786–27792PubMedCrossRefGoogle Scholar
  11. 11.
    Chavanas S, Mechin MC, Takahara H et al. (2004) Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene 330:19–27PubMedCrossRefGoogle Scholar
  12. 12.
    Liu GY, Liao YF, Chang WH et al. (2006) Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells. Apoptosis 11:183–196PubMedCrossRefGoogle Scholar
  13. 13.
    Nijenhuis S, Zendman AJ, Vossenaar ER, Pruijn GJ, vanVenrooij WJ (2004) Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and biochemical aspects of an RA-specific marker. Clin Chim Acta 350:17–34PubMedCrossRefGoogle Scholar
  14. 14.
    Chang X, Yamada R, Suzuki A et al. (2005) Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 44:40–50CrossRefGoogle Scholar
  15. 15.
    Senshu T, Akiyama K, Ishigami A, Nomura K (1999) Studies on specificity of peptidylarginine deiminase reactions using an immunochemical probe that recognizes an enzymatically deiminated partial sequence of mouse keratin K1. J Dermatol Sci 21:113–126PubMedCrossRefGoogle Scholar
  16. 16.
    Ishida-Yamamoto A, Senshu T, Eady RA et al. (2002) Sequential reorganization of cornified cell keratin filaments involving filaggrin-mediated compaction and keratin 1 deimination. J Invest Dermatol 118:282–287PubMedCrossRefGoogle Scholar
  17. 17.
    Tarcsa E, Marekov LN, Mei G, Melino G, Lee SC, Steinert PM (1996) Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 271:30709–30716PubMedCrossRefGoogle Scholar
  18. 18.
    Vossenaar ER, Radstake TR, Van Der Heijden A et al. (2004) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63:373–381PubMedCrossRefGoogle Scholar
  19. 19.
    Moscarello MA, Wood DD, Ackerley C, Boulias C (1994) Myelin in multiple sclerosis is developmentally immature. J Clin Invest 94:146–154PubMedGoogle Scholar
  20. 20.
    Wang Y, Wysocka J, Sayegh J et al. (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283PubMedCrossRefGoogle Scholar
  21. 21.
    Cuthbert GL, Daujat S, Snowden A et al. (2004) Histone deimination antagonizes arginine methylation. Cell 118:545–553PubMedCrossRefGoogle Scholar
  22. 22.
    Vossenaar ER, Nijenhuis S, Helsen MM et al. (2003) Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48:2489–2500PubMedCrossRefGoogle Scholar
  23. 23.
    Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E et al. (2001) The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 166:4177–4184PubMedGoogle Scholar
  24. 24.
    Suzuki A, Yamada R, Ohtake-Yamanaka M, Okazaki Y, Sawada T, Yamamoto K (2005) Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis. Biochem Biophys Res Commun 333:418–426PubMedCrossRefGoogle Scholar
  25. 25.
    Kinloch A, Tatzer V, Wait R et al. (2005) Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res Ther 7:1421–1429CrossRefGoogle Scholar
  26. 26.
    Chang X, Yamada R, Sawada T, Suzuki A, Kochi Y, Yamamoto K (2005) The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 44:293–298CrossRefGoogle Scholar
  27. 27.
    Okazaki Y, Suzuki A, Sawada T et al. (2006) Identification of citrullinated eukaryotic translation initiation factor 4G1 as novel autoantigen in rheumatoid arthritis. Biochem Biophys Res Commun 341:94–100PubMedCrossRefGoogle Scholar
  28. 28.
    Wood DD, Bilbao JM, O’Connors P, Moscarello MA (1996) Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann Neurol 40:18–24PubMedCrossRefGoogle Scholar
  29. 29.
    Wright PW, Bolling LC, Calvert ME et al. (2003) ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Dev Biol 256:73–88PubMedCrossRefGoogle Scholar
  30. 30.
    Asaga H, Yamada M, Senshu T (1998) Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243:641–646PubMedCrossRefGoogle Scholar
  31. 31.
    Mizoguchi M, Manabe M, Kawamura Y et al. (1998) Deimination of 70-kD nuclear protein during epidermal apoptotic events in vitro. J Histochem Cytochem 46:1303–1309PubMedGoogle Scholar
  32. 32.
    Senshu T, Akiyama K, Nagata S, Watanabe K, Hikichi K (1989) Peptidylarginine deiminase in rat pituitary: sex difference, estrous cycle-related changes, and estrogen dependence. Endocrinology 124:2666–2670PubMedCrossRefGoogle Scholar
  33. 33.
    Okuda M (2002) The role of nucleophosmin in centrosome duplication. Oncogene 21:6170–6174PubMedCrossRefGoogle Scholar
  34. 34.
    Hingorani K, Szebeni A, Olson MO (2000) Mapping the functional domains of nucleolar protein B23. J Biol Chem 275:24451–24457PubMedCrossRefGoogle Scholar
  35. 35.
    Takemura M, Ohoka F, Perpelescu M et al. (2002) Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23. Exp Cell Res 276:233–241PubMedCrossRefGoogle Scholar
  36. 36.
    Hagiwara T, Nakashima K, Hirano H, Senshu T, Yamada M (2002) Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. Biochem Biophys Res Commun 290:979–983PubMedCrossRefGoogle Scholar
  37. 37.
    Hagiwara T, Hidaka Y, Yamada M (2005) Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes. Biochemistry 44:5827–5834PubMedCrossRefGoogle Scholar
  38. 38.
    Liu H, Pope RM (2003) The role of apoptosis in rheumatoid arthritis. Curr Opin Pharmacol 3:317–322PubMedCrossRefGoogle Scholar
  39. 39.
    Kang CP, Lee HS, Ju H, Cho H, Kang C, Bae SC (2006) A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum 54:90–96PubMedCrossRefGoogle Scholar
  40. 40.
    Liu GY, Hung YC, Hsu PC et al. (2005) Ornithine decarboxylase prevents tumor necrosis factor alpha-induced apoptosis by decreasing intracellular reactive oxygen species. Apoptosis 10:569– 581PubMedCrossRefGoogle Scholar
  41. 41.
    Huang CC, Hsu PC, Hung YC et al. (2005) Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis 10:895–907PubMedCrossRefGoogle Scholar
  42. 42.
    Liao YF, Hsieh HC, Liu GY, Hung HC (2005) A continuous spectrophotometric assay method for peptidylarginine deiminase type 4 activity. Anal Biochem 347:176–181PubMedCrossRefGoogle Scholar
  43. 43.
    Boyde TR, Rahmatullah M (1980) Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime. Anal Biochem 107:424–431PubMedCrossRefGoogle Scholar
  44. 44.
    Cheng WH, Quimby FW, Lei XG (2003) Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. Free Radic Biol Med 34:918– 927PubMedCrossRefGoogle Scholar
  45. 45.
    Jamison JM, Gilloteaux J, Taper HS, Calderon PB, Summers JL (2002) Autoschizis: a novel cell death. Biochem Pharmacol 63:1773–1783PubMedCrossRefGoogle Scholar
  46. 46.
    Skulachev VP (2006) Bioenergetic aspects of apoptosis, necrosis and mitoptosis. Apoptosis 11:473–485PubMedCrossRefGoogle Scholar
  47. 47.
    Grossmann J (2002) Molecular mechanisms of “detachment-induced apoptosis–Anoikis”. Apoptosis 7:247–260PubMedCrossRefGoogle Scholar
  48. 48.
    Lum JJ, Bauer DE, Kong M et al. (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120:237–248PubMedCrossRefGoogle Scholar
  49. 49.
    Levine B (2005) Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120:159–162PubMedGoogle Scholar
  50. 50.
    Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M (2004) Structural basis for Ca(2+)-induced activation of human PAD4. Nat Struct Mol Biol 11:777–783PubMedCrossRefGoogle Scholar
  51. 51.
    Inagaki M, Takahara H, Nishi Y, Sugawara K, Sato C (1989). Ca2+-dependent deimination-induced disassembly of intermediate filaments involves specific modification of the amino-terminal head domain. J Biol Chem 264:18119–18127PubMedGoogle Scholar
  52. 52.
    Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568PubMedCrossRefGoogle Scholar
  53. 53.
    Appella E, Anderson CW (2000) Signaling to p53: breaking the posttranslational modification code. Pathol Biol (Paris) 48:227–245Google Scholar
  54. 54.
    Munoz-Alonso MJ, Acosta JC, Richard C, Delgado MD, Sedivy J, Leon J (2005) p21Cip1 and p27Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J Biol Chem 280:18120–18129PubMedCrossRefGoogle Scholar
  55. 55.
    Norbury CJ, Zhivotovsky B (2004) DNA damage-induced apoptosis. Oncogene 23:2797–2808PubMedCrossRefGoogle Scholar
  56. 56.
    Itoh K, Hase H, Kojima H, Saotome K, Nishioka K, Kobata T (2004) Central role of mitochondria and p53 in Fas-mediated apoptosis of rheumatoid synovial fibroblasts. Rheumatology (Oxford) 43:277–285CrossRefGoogle Scholar
  57. 57.
    Schuler M, Green DR (2005) Transcription, apoptosis and p53: catch-22. Trends Genet 21:182–187PubMedCrossRefGoogle Scholar
  58. 58.
    Chipuk JE, Kuwana T, Bouchier-Hayes L et al. (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014PubMedCrossRefGoogle Scholar
  59. 59.
    Salmon M, Scheel-Toellner D, Huissoon AP et al. (1997) Inhibition of T cell apoptosis in the rheumatoid synovium. J Clin Invest 99:439–446PubMedCrossRefGoogle Scholar
  60. 60.
    Denny MF, Chandaroy P, Killen PD et al. (2006) Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. J Immunol 176:2095–2104PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Life SciencesNational Chung-Hsing UniversityTaichungTaiwan, ROC
  2. 2.Institute of ImmunologyChung-Shan Medical UniversityTaichungTaiwan, ROC
  3. 3.Department of MedicineDa-Chien General HospitalMiao-LiTaiwan, ROC
  4. 4.Department of Internal Medicine, Chung-Shan Medical University Hospital and Institute of ImmunologyChung-Shan Medical UniversityTaichungTaiwan, ROC

Personalised recommendations