Abstract
Peptidylarginine deiminases (PADs or PADIs) are a family of calcium-dependent enzymes that post-translationally convert positively charged arginine residues to neutrally charged citrulline in a process called citrullination or deimination. There are five PAD family members (PAD1–PAD4 and PAD6). PAD genes arose by duplication and are clustered within a ~300-kb region on chromosome 1p36 in humans and within a ~230-kb region on chromosome 4 in mice. In both species PAD1, PAD3, PAD4, and PAD6 are grouped closely together and are oriented in the same direction, while PAD2 is set apart from the other PADs by at least 60 kb and is oriented in the opposite direction (Vossenaar et al. 2003). PAD isozymes are expressed in a range of tissues in mammals, with PAD2 being broadly expressed in numerous tissues, while PAD4 is highly represented in immune cells. PAD6 expression, on the other hand, is primarily limited to oocytes and early embryos, whereas PAD1 and PAD3 appear to be mainly expressed in the epidermis. While still coming to light, functional roles for PADs in mammalian physiology and pathology are diverse and include cellular differentiation, nerve growth, apoptosis, inflammation, gene regulation, and early embryonic development. Over the last several years, investigators have generated genetically engineered mice (GEM) for PAD2, PAD3, PAD4, and PAD6 to investigate the functions of these unique enzymes at the organismal level. Outcomes from these studies are highlighted in Fig. 4.1, and the goal of this chapter is to provide a broad summary of findings obtained from these animals.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Akiyama, K., Sakurai, Y., Asou, H., & Senshu, T. (1999). Localization of peptidylarginine deiminase type II in a stage-specific immature oligodendrocyte from rat cerebral hemisphere. Neuroscience Letters, 274(1), 53–55.
Bawadekar, M., Shim, D., Johnson, C. J., Warner, T. F., Rebernick, R., Damgaard, D., Nielsen, C. H.,Pruijn, G. J. M., Nett, J. E., & Shelef, M. A. (2017). Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation. Journal of Autoimmunity, 80, 39–47.
Begovich, A. B., Carlton, V. E. H., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C., Ardlie, K. G., Huang, Q., Smith, A. M., Spoerke, J. M., Conn, M. T., Chang, M.,Chang, S.-Y. P., Saiki, R. K., Catanese, J. J., Leong, D. U., Garcia, V. E., McAllister, L. B., Jeffery, D. A., Lee, A. T., Batliwalla, F., Remmers, E., Criswell, L. A., Seldin, M. F., Kastner, D. L., Amos, C. I., Sninsky, J. J., & Gregersen, P. K. (2004). A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. The American Journal of Human Genetics, 75(2), 330–337.
Brinkmann, V., & Zychlinsky, A. (2012). Neutrophil extracellular traps: Is immunity the second function of chromatin? The Journal of Cell Biology, 198(5), 773–783.
Coudane, F., Mechin, M.-C., Huchenq, A., Henry, J., Nachat, R., Ishigami, A., Adoue, V., Sebbag, M.,Serre, G., & Simon, M. (2011). Deimination and expression of peptidylarginine deiminases during cutaneous wound healing in mice. European Journal of Dermatology, 21(3), 376–384. [cited 2017 Feb 10]. Retrieved from PMID: 21697043. http://www.ncbi.nlm.nih.gov/pubmed/21697043.
Damgaard, D., Friberg, M., Nielsen, B., Quisgaard Gaunsbaek, M., Palarasah, Y., Svane-Knudsen, V.,Nielsen, C. H., Friberg, M., Gaunsbaek, M. Q., Palarasah, Y., Svane-Knudsen, V., & Nielsen, C. H. (2015). Smoking is associated with increased levels of extra-cellular peptidylarginine deiminase 2 (PAD2) in the lungs. Clinical and Experimental Rheumatology, 33(3), 405–408.
Darrah, E., Rosen, A., Giles, J. T., & Andrade, F. (2012). Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis. Annals of the Rheumatic Diseases, 71(1), 92–98. BMJ Publishing Group Ltd. [cited 2017 Feb 21]. PMID: 21859690. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21859690.
Erpenbeck, L., Chowdhury, C. S., Zsengeller, Z. K., Gallant, M., Burke, S. D., Cifuni, S., Hahn, S.,Wagner, D. D., & Karumanchi, S. A. (2016). PAD4 deficiency decreases inflammation and susceptibility to pregnancy loss in a mouse model. Biology of Reproduction, 95(6), 132. Oxford University Press. [cited 2017 Feb 27]. Retrieved from https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.116.140293.
Esposito, G., Vitale, A. M., Leijten, F. P. J., Strik, A. M., Koonen-Reemst, A. M. C. B., Yurttas, P., Robben, T. J. A. A., Coonrod, S., & Gossen, J. A. (2007). Peptidylarginine deiminase (PAD) 6 is essential for oocyte cytoskeletal sheet formation and female fertility. Molecular and Cellular Endocrinology, 273(1–2), 25–31. [cited 2017 Feb 22]. PMID: 17587491. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17587491.
Feldmann, M., & Maini, R. N. (2003). TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nature Medicine, 9(10), 1245–1250. Nature Publishing Group. [cited 2017 Mar 1]. Retrieved from http://www.nature.com/doifinder/10.1038/nm939.
Ferrari-Lacraz, S., Sebbag, M., Chicheportiche, R., Foulquier, C., Serre, G., & Dayer, J.-M. (2012). Contact with stimulated T cells up-regulates expression of peptidylarginine deiminase 2 and 4 by human monocytes. European Cytokine Network, 23(2), 36–44. [cited 2017 Feb 21]. PMID: 22614825. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22614825.
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. (2007). 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. Arthritis and Rheumatism, 56(11), 3541–3553. Wiley Subscription Services, Inc., A Wiley Company. [cited 2017 Feb 21]. Retrieved from http://doi.wiley.com/10.1002/art.22983.
Hemmers, S., Teijaro, J. R., Arandjelovic, S., & Mowen, K. A. (2011). PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. PLoS One, 6(7), e22043. Coonrod SA, editor. Public Library of Science. [cited 2017 Feb 23]. Retrieved from http://dx.plos.org/10.1371/journal.pone.0022043.
Horibata, S., Coonrod, S. A., & Cherrington, B. D. (2012). Role for peptidylarginine deiminase enzymes in disease and female reproduction. The Journal of Reproduction and Development, 58, 274–282.
Kan, R., Yurttas, P., Kim, B., Jin, M., Wo, L., Lee, B., Gosden, R., & Coonrod, S. A. (2011). Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices. Developmental Biology, 350(2), 311–322.
Kan, R., Jin, M., Subramanian, V., Causey, C. P., Thompson, P. R., & Coonrod, S. A. (2012). Potential role for PADI-mediated histone citrullination in preimplantation development. BMC Developmental Biology, 12(1), 19. BioMed Central. [cited 2017 Feb 24]. Retrieved from http://bmcdevbiol.biomedcentral.com/articles/10.1186/1471-213X-12-19.
Kaplan, M. J., & Radic, M. (2012). Neutrophil extracellular traps: Double-edged swords of innate immunity. Journal of Immunology, 189(6), 2689–2695. NIH Public Access. [cited 2017 Feb 23]. PMID: 22956760. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22956760.
Khandpur, R., Carmona-Rivera, C., Vivekanandan-Giri, A., Gizinski, A., Yalavarthi, S., Knight, J. S., Friday, S., Li, S., Patel, R. M., Subramanian, V., Thompson, P., Chen, P., Fox, D. A., Pennathur, S., & Kaplan, M. J. (2013). NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Science Translational Medicine, 5(178), 178ra40.
Kolaczkowska, E., Jenne, C. N., Surewaard, B. G. J., Thanabalasuriar, A., Lee, W.-Y., Sanz, M.-J., Mowen, K., Opdenakker, G., & Kubes, P. (2015). Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nature Communications, 6, 6673. Nature Publishing Group. [cited 2017 Feb 24]. Retrieved from http://www.nature.com/doifinder/10.1038/ncomms7673.
Li, P., Li, M., Lindberg, M. R., Kennett, M. J., Xiong, N., & Wang, Y. (2010). PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. The Journal of Experimental Medicine, 207(9), 1853–1862. The Rockefeller University Press. [cited 2017 Feb 23]. PMID: 20733033. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20733033.
Maddirevula, S., Coskun, S., Awartani, K., Alsaif, H., Abdulwahab, F. M., & Alkuraya, F. S. (2017). The human knockout phenotype of PADI6 is female sterility caused by cleavage failure of their fertilized eggs. Clinical Genetics, 91(2), 344–345. Blackwell Publishing Ltd. [cited 2017 Feb 22]. Retrieved from http://doi.wiley.com/10.1111/cge.12866.
Martinod, K., & Wagner, D. D. (2014). Thrombosis: Tangled up in NETs. Blood, 123(18), 2768–2776.
Martinod, K., Demers, M., Fuchs, T. A., Wong, S. L., Brill, A., Gallant, M., Hu, J., Wang, Y., & Wagner, D. D. (2013). Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proceedings of the National Academy of Sciences of the United States of America, 110(21), 8674–8679. National Academy of Sciences. [cited 2017 Feb 23]. PMID: 23650392. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23650392.
Martinod, K., Fuchs, T. A., Zitomersky, N. L., Wong, S. L., Demers, M., Gallant, M., Wang, Y., & Wagner, D. D. (2015). PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood, 125(12), 1948–1956.
Mastronardi, F. G., Wood, D. D., Mei, J., Raijmakers, R., Tseveleki, V., Dosch, H.-M., Probert, L., Casaccia-Bonnefil, P., & Moscarello, M. A. (2006). Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: A role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. The Journal of Neuroscience, 26(44), 11387–11396.
McElwee, J. L., Mohanan, S., Horibata, S., Sams, K. L., Anguish, L. J., McLean, D., Cvita, I., Wakshlag, J. J., & Coonrod, S. A. (2014). PAD2 overexpression in transgenic mice promotes spontaneous skin neoplasia. Cancer Research, 74(21), 6306–6317. [cited 2017 Feb 1]. PMID: 25213324. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25213324.
Musse, A. A., Li, Z., Ackerley, C. A., Bienzle, D., Lei, H., Poma, R., Harauz, G., Moscarello, M. A., & Mastronardi, F. G. (2008). Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Disease Models & Mechanisms, 1(4–5), 229–240. Company of Biologists. [cited 2017 Feb 10]. PMID: 19093029. Retrieved from http://www.ncbi.nlm. nih.gov/pubmed/19093029.
Raijmakers, R., Vogelzangs, J., Raats, J., Panzenbeck, M., Corby, M., Jiang, H., Thibodeau, M., Haynes, N., Van Venrooij, W. J., Pruijn, G. J. M., & Werneburg, B. (2006). Experimental autoimmune encephalomyelitis induction in peptidylarginine deiminase 2 knockout mice. Journal of Comparative Neurology, 498(2), 217–226. Wiley Subscription Services, Inc., A Wiley Company. [cited 2017 Feb 10]. Retrieved from http://doi.wiley.com/10.1002/cne.21055.
Rohrbach, A. S., Hemmers, S., Arandjelovic, S., Corr, M., & Mowen, K. A. (2012). PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis. Arthritis Research & Therapy, 14, R104.
Savchenko, A. S., Borissoff, J. I., Martinod, K., De Meyer, S. F., Gallant, M., Erpenbeck, L., Brill, A.,Wang, Y., & Wagner, D. D. (2014). VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood, 123(1), 141–148.
Seri, Y., Shoda, H., Suzuki, A., Matsumoto, I., Sumida, T., Fujio, K., & Yamamoto, K. (2015). Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model. Scientific Reports, 5, 13041. Nature Publishing Group. [cited 2017 Feb 24]. Retrieved from http://www.nature.com/articles/srep13041.
Shelef, M. A., Sokolove, J., Lahey, L. J., Wagner, C. A., Sackmann, E. K., Warner, T. F., Wang, Y., Beebe, D. J., Robinson, W. H., & Huttenlocher, A. (2014). Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis. Arthritis & Rhematology, 66(6), 1482–1491. [cited 2017 Feb 23]. Retrieved from http://doi.wiley.com/ 10.1002/art.38393.
Sokolove, J., Zhao, X., Chandra, P. E., & Robinson, W. H. (2011). Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis and Rheumatism, 63(1), 53–62. [cited 2017 Feb 23]. PMID: 20954191. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20954191.
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. (2003). Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nature Genetics, 34(4), 395–402. Nature Publishing Group. [cited 2017 Feb 23]. Retrieved from http://www.nature.com/doifinder/10.1038/ng1206.
Suzuki, A., Kochi, Y., Shoda, H., Seri, Y., Fujio, K., Sawada, T., Yamada, R., & Yamamoto, K. (2016). Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Musculoskeletal Disorders, 17(1), 205. BioMed Central. [cited 2017 Feb 24]. Retrieved from http://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-016-1055-2.
Taki, H., Gomi, T., Knuckley, B., Thompson, P. R., Vugrek, O., Hirata, K., Miyahara, T., Shinoda, K.,Hounoki, H., Sugiyama, E., Usui, I., Urakaze, M., Tobe, K., Ishimoto, T., Inoue, R., Tanaka, A.,Mano, H., Ogawa, H., & Mori, H. (2011). Purification of enzymatically inactive peptidylarginine deiminase type 6 from mouse ovary that reveals hexameric structure different from other dimeric isoforms. Advances in Bioscience and Biotechnology, 2(4), 304–310. Scientific Research Publishing. [cited 2017 Feb 24]. Retrieved from http://www.scirp.org/journal/PaperDownload.aspx? DOI=10.4236/abb.2011.24044.
Ü Basmanav, F. B., Cau, L., Tafazzoli, A., Méchin, M.-C., Wolf, S., Romano, M. T., Valentin, F.,Wiegmann, H., Huchenq, A., Kandil, R., Garcia Bartels, N., Kilic, A., George, S., Ralser, D. J.,Bergner, S., Ferguson, D. J. P., Oprisoreanu, A.-M., Wehner, M., Thiele, H., Altmüller, J., Nürnberg, P., Swan, D., Houniet, D., Büchner, A., Weibel, L., Wagner, N., Grimalt, R., Bygum, A.,Serre, G., Blume-Peytavi, U., Sprecher, E., Schoch, S., Oji, V., Hamm, H., Farrant, P., Simon, M., & Betz, R. C. (2016). Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome. American Journal of Human Genetics, 99(6), 1292–1304.
van Beers, J. J. B. C., Zendman, A. J. W., Raijmakers, R., Stammen-Vogelzangs, J., & Pruijn, G. J. M.(2013). Peptidylarginine deiminase expression and activity in PAD2 knock-out and PAD4-low mice. Biochimie, 95(2), 299–308.
van Gaalen, F. A., Linn-Rasker, S. P., van Venrooij, W. J., de Jong, B. A., Breedveld, F. C., Verweij, C. L.,Toes, R. E. M., & Huizinga, T. W. J. (2004). Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: A prospective cohort study. Arthritis and Rheumatism, 50(3), 709–715. Wiley Subscription Services, Inc., A Wiley Company. [cited 2017 Mar 1]. Retrieved from http://doi.wiley.com/10.1002/art.20044.
Vossenaar, E. R., Zendman, A. J. W., van Venrooij, W. J., & Pruijn, G. J. M. (2003). PAD, a growing family of citrullinating enzymes: Genes, features and involvement in disease. BioEssays, 25(11), 1106–1118. Wiley Subscription Services, Inc., A Wiley Company. Retrieved from http://doi.wiley.com/10.1002/bies.10357.
Vossenaar, E. R., Radstake, T. R. D., van der Heijden, A., van Mansum, M. A. M., Dieteren, C., de Rooij, D.-J., Barrera, P., Zendman, A. J. W., & van Venrooij, W. J. (2004). Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Annals of the Rheumatic Diseases, 63(4), 373–381. [cited 2017 Feb 21]. PMID: 15020330. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15020330.
Wang, Y., Li, M., Stadler, S., Correll, S., Li, P., Wang, D., Hayama, R., Leonelli, L., Han, H., Grigoryev, S. A., Allis, C. D., & Coonrod, S. A. (2009). Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. The Journal of Cell Biology, 184(2), 205–213. [cited 2017 Feb 23]. PMID: 19153223. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19153223.
Wood, D. D., Ackerley, C. A., Van Den Brand, B., Zhang, L., Raijmakers, R., Mastronardi, F. G., & Moscarello, M. A. (2008). Myelin localization of peptidylarginine deiminases 2 and 4: Comparison of PAD2 and PAD4 activities. Laboratory Investigation, 88, 354–364.
Wright, P. W., Bolling, L. C., Calvert, M. E., Sarmento, O. F., Berkeley, E. V., Shea, M. C., Hao, Z.,Jayes, F. C., Bush, L. A., Shetty, J., Shore, A. N., Reddi, P. P., Tung, K. S., Samy, E., Allietta, M. M., Sherman, N. E., Herr, J. C., & Coonrod, S. A. (2003). ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Developmental Biology, 256(1), 73–88. [cited 2017 Feb 22]. PMID: 12654293. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12654293.
Xu, Y., Shi, Y., Fu, J., Yu, M., Feng, R., Sang, Q., Liang, B., Chen, B., Qu, R., Li, B., Yan, Z., Mao, X.,Kuang, Y., Jin, L., He, L., Sun, X., & Wang, L. (2016). Mutations in PADI6 cause female infertility characterized by early embryonic arrest. American Journal of Human Genetics, 99(3), 744–752. [cited 2017 Feb 22]. Retrieved from http://linkinghub.elsevier.com/retrieve/pii/S0002929716302282.
Ying, S., Dong, S., Kawada, A., Kojima, T., Phane Chavanas, S., Mé Chin, M.-C., Ronique Adoue, V.,Serre, G., Simon, M., & Takahara, H. (2009). Transcriptional regulation of peptidylarginine deiminase expression in human keratinocytes. Journal of Dermatological Science, 53(1), 2–9.
Yurttas, P., Vitale, A. M., Fitzhenry, R. J., Cohen-Gould, L., Wu, W., Gossen, J. A., & Coonrod, S. A.(2008). Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Development, 135(15), 2627–2636.
Zhang, X., Liu, X., Zhang, M., Li, T., Muth, A., Thompson, P. R., Coonrod, S. A., & Zhang, X.(2016). Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development. Scientific Reports, 6, 38727. Nature Publishing Group. [cited 2017 Feb 24]. PMID: 27929094. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/27929094.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Mukai, C., Marks, B.A., Coonrod, S.A. (2017). The Use of Genetically Engineered Mice to Study PAD Biology and Pathology. In: Nicholas, A., Bhattacharya, S., Thompson, P. (eds) Protein Deimination in Human Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-58244-3_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-58244-3_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-58243-6
Online ISBN: 978-3-319-58244-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)