Protein arginine deiminase 4 (PAD4) catalyzes the conversion of arginine residues to citrulline within cellular protein substrates, resulting in the loss of a positive charge, which can alter protein structure and/or function. It is expressed in neutrophils, as well as a variety of tissues, including the brain, liver, lung, and kidney. PAD4 has a key role in NETosis, a lytic form of cell death characterized by the release of neutrophil extracellular traps (NETs). Upon neutrophil activation, PAD4 translocates to the nucleus where it citrullinates histones, initiating chromatin decondensation and the release of NETs. Neutrophils isolated from Pad4-/- mice exhibit decreased citrullination of histone H3 under both basal and LPS-stimulated conditions and are defective for NET formation in response to stimulation with LPS, phorbol 12-myristate 13-acetate (PMA; ), or hydrogen peroxide. Pad4-/- mice exhibit larger lesions than wild-type mice in a model of necrotizing fasciitis induced by M1 group A S. pyogenes lacking the extracellular DNase Sda1. Pad4-deficient mice also exhibit reduced infarct size in a model of myocardial ischemia-reperfusion injury and reduced tumor growth in a Lewis lung carcinoma model. PADI4 SNPs, including G55S, V82A, and G112A, are associated with rheumatoid arthritis in humans. Cayman’s PAD4 (human, recombinant) protein contains the G55S, V82A, and G112A SNPs and can be used for enzyme activity assays.
