Peptidylarginine Deiminases (PADs) catalyze the post-translational conversion of arginine residues to citrulline. PAD4 is localized to the nucleus of neutrophils where it citrullinates the core histones H3, H4 and H2A. PAD4-mediated histone citrullination is required for the generation of Neutrophil Extracellular Traps (NETs), aggregates of DNA and anti-microbial proteins that are expelled from neutrophils to ensnare and kill bacteria. The majority of patients with Rheumatoid Arthritis (RA) produce antibodies to citrullinated proteins, suggesting a role for PAD4 in the pathogenesis of this disease.
PAD4 has also been recognized as a transcriptional coregulator. It is recruited to the promoters of genes regulated by the estrogen receptor (ER) and p53, where it catalyzes the citrullination of the N-terminal portion of histone H3 and inhibits arginine methylation. Recently, it was reported that a member of the ETS oncogene family, Elk-1 is citrullinated by PAD4 to activate c-fos expression in breast cancer cells.
References:
Jones JE, Causey CP, Knuckley B, Slack-Noyes JL, Thompson PR. Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential. Curr Opin Drug Discov Devel. 2009 Sep;12(5):616-27. PMID: 19736621; PMCID: PMC3771078.
Rohrbach AS, Slade DJ, Thompson PR, Mowen KA. Activation of PAD4 in NET formation. Front Immunol. 2012;3:360. Published 2012 Nov 29. doi:10.3389/fimmu.2012.00360
Urano T, Nakayama M, Ohara O, Yamamura K, Yamamoto K, Miyazaki T. PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression. Nat Commun. 2013;4:1836. doi: 10.1038/ncomms2862. PMID: 23673621; PMCID: PMC3674250.
Koushik S, Joshi N, Nagaraju S, Mahmood S, Mudeenahally K, Padmavathy R, Jegatheesan SK, Mullangi R, Rajagopal S. PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin Ther Targets. 2017 Apr;21(4):433-447. doi: 10.1080/14728222.2017.1294160. Epub 2017 Feb 22. PMID: 28281906.
Nakashima K, Arai S, Suzuki A, Nariai Y, Urano T, Nakayama M, Ohara O, Yamamura K, Yamamoto K, Miyazaki T. PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression. Nat Commun. 2013;4:1836. doi: 10.1038/ncomms2862. PMID: 23673621; PMCID: PMC3674250.
