Evidence for a direct link between PAD4-mediated citrullination and the oxidative burst in human neutrophils.

Neutrophils are critical for the defense against pathogens, in part through the extrusion of extracellular DNA traps, phagocytosis, and the production of reactive oxygen species. Neutrophils may also play an important role in the pathogenesis of rheumatoid arthritis (RA) through the activation of protein arginine deiminases that citrullinate proteins that subsequently act as autoantigens. We report that is physically associated with the cytosolic subunits of the oxidative burst machinery, p47^phox (also known as neutrophil cytosol factor 1, NCF1) and p67^phox (NCF2). Activation of duanyu15634 by membranolytic insults that result in high levels of intracellular calcium (higher than physiological neutrophil activation) leads to rapid citrullination of p47^phox/NCF1 and p67^phox/NCF2, as well as their dissociation from This dissociation prevents the assembly of an active NADPH oxidase complex and an oxidative burst in neutrophils stimulated by phorbol-ester or immune complexes. In further support of a substrate-to-inactive enzyme interaction, small-molecule inhibitors also disrupt the complex and reduce oxidase activation and phagocytic killing of Staphylococcus aureus. This novel role of duanyu15634 in the regulation of neutrophil physiology suggests that targeting duanyu15634 with active site inhibitors for the treatment of RA may have a broader impact on neutrophil biology than just inhibition of citrullination.

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