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Gene Review

PADI4  -  peptidyl arginine deiminase, type IV

Homo sapiens

Synonyms: HL-60 PAD, PAD, PAD4, PADI5, PDI4, ...
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Disease relevance of PADI4


High impact information on PADI4

  • Deimination by PADI4 prevents arginine methylation by CARM1 [4].
  • Consistent with a repressive role for PADI4, this enzyme is recruited to the pS2 promoter following hormone induction when the gene is transcriptionally downregulated [4].
  • We show that peptidyl arginine deiminase 4 (PADI4) specifically deiminates, arginine residues R2, R8, R17, and R26 in the H3 tail [4].
  • PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues [5].
  • Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease [5].

Biological context of PADI4

  • All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes [6].
  • Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans [7].
  • We also found extracellular and intracellular expression of PADI4 in fibrin deposits with loose tissue structures where apoptosis was widespread [8].
  • Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated [9].
  • Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis (RA) in the Japanese population [9].

Anatomical context of PADI4


Physical interactions of PADI4

  • It was indicated that estrogen stimulated PADI4 expression through binding of estrogen receptor (ER)-alpha to the upstream of the PADI4 gene and ERalpha-mediated enhancement of activator protein-1, Sp1, and nuclear factor-Y levels [12].

Other interactions of PADI4

  • We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P=.001) and PADI4 (PADI4_94, OR 1.24; P=.001) with the development of RA, but only in the NARAC cohort [13].
  • Comparison of enzymatic properties between hPADI2 and hPADI4 [14].
  • We aimed to determine whether PADI4 constitutes an autoantigen in RA [15].
  • The aim of this study was to analyse the role of PADI4 gene in conferring susceptibility to MS, by means of a family-based association study, testing three SNPs by RFLP [1].

Analytical, diagnostic and therapeutic context of PADI4


  1. PADI4 gene in multiple sclerosis: a family-based association study. Tommasi, C., Petit-Teixeira, E., Cournu-Rebeix, I., Caponi, L., Pierlot, C., Fontaine, B., Cornelis, F., Migliorini, P. J. Neuroimmunol. (2006) [Pubmed]
  2. Investigation of polymorphisms in the PADI4 gene in determining severity of inflammatory polyarthritis. Barton, A., Bowes, J., Eyre, S., Symmons, D., Worthington, J., Silman, A. Ann. Rheum. Dis. (2005) [Pubmed]
  3. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Foulquier, C., Sebbag, M., Clavel, C., Chapuy-Regaud, S., Al Badine, R., Méchin, M.C., Vincent, C., Nachat, R., Yamada, M., Takahara, H., Simon, M., Guerrin, M., Serre, G. Arthritis Rheum. (2007) [Pubmed]
  4. Histone deimination antagonizes arginine methylation. Cuthbert, G.L., Daujat, S., Snowden, A.W., Erdjument-Bromage, H., Hagiwara, T., Yamada, M., Schneider, R., Gregory, P.D., Tempst, P., Bannister, A.J., Kouzarides, T. Cell (2004) [Pubmed]
  5. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M., Nagasaki, M., Nakayama-Hamada, M., Kawaida, R., Ono, M., Ohtsuki, M., Furukawa, H., Yoshino, S., Yukioka, M., Tohma, S., Matsubara, T., Wakitani, S., Teshima, R., Nishioka, Y., Sekine, A., Iida, A., Takahashi, A., Tsunoda, T., Nakamura, Y., Yamamoto, K. Nat. Genet. (2003) [Pubmed]
  6. Association between PADI4 and rheumatoid arthritis: a replication study. Ikari, K., Kuwahara, M., Nakamura, T., Momohara, S., Hara, M., Yamanaka, H., Tomatsu, T., Kamatani, N. Arthritis Rheum. (2005) [Pubmed]
  7. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Kang, C.P., Lee, H.S., Ju, H., Cho, H., Kang, C., Bae, S.C. Arthritis Rheum. (2006) [Pubmed]
  8. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Chang, X., Yamada, R., Suzuki, A., Sawada, T., Yoshino, S., Tokuhiro, S., Yamamoto, K. Rheumatology (Oxford, England) (2005) [Pubmed]
  9. Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case-control study. Hoppe, B., Häupl, T., Gruber, R., Kiesewetter, H., Burmester, G.R., Salama, A., Dörner, T. Arthritis Res. Ther. (2006) [Pubmed]
  10. Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells. Liu, G.Y., Liao, Y.F., Chang, W.H., Liu, C.C., Hsieh, M.C., Hsu, P.C., Tsay, G.J., Hung, H.C. Apoptosis (2006) [Pubmed]
  11. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). Nakashima, K., Hagiwara, T., Ishigami, A., Nagata, S., Asaga, H., Kuramoto, M., Senshu, T., Yamada, M. J. Biol. Chem. (1999) [Pubmed]
  12. Estrogen-enhanced peptidylarginine deiminase type IV gene (PADI4) expression in MCF-7 cells is mediated by estrogen receptor-alpha-promoted transfactors activator protein-1, nuclear factor-Y, and Sp1. Dong, S., Zhang, Z., Takahara, H. Mol. Endocrinol. (2007) [Pubmed]
  13. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Plenge, R.M., Padyukov, L., Remmers, E.F., Purcell, S., Lee, A.T., Karlson, E.W., Wolfe, F., Kastner, D.L., Alfredsson, L., Altshuler, D., Gregersen, P.K., Klareskog, L., Rioux, J.D. Am. J. Hum. Genet. (2005) [Pubmed]
  14. Comparison of enzymatic properties between hPADI2 and hPADI4. Nakayama-Hamada, M., Suzuki, A., Kubota, K., Takazawa, T., Ohsaka, M., Kawaida, R., Ono, M., Kasuya, A., Furukawa, H., Yamada, R., Yamamoto, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  15. Peptidylarginine deiminase 4 (PADI4) identified as a conformation-dependent autoantigen in rheumatoid arthritis. Takizawa, Y., Sawada, T., Suzuki, A., Yamada, R., Inoue, T., Yamamoto, K. Scand. J. Rheumatol. (2005) [Pubmed]
  16. Genetic and genomic studies of PADI4 in rheumatoid arthritis. Harney, S.M., Meisel, C., Sims, A.M., Woon, P.Y., Wordsworth, B.P., Brown, M.A. Rheumatology (Oxford, England) (2005) [Pubmed]
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