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.
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