Peptidylarginine deiminases: physiological function, interaction with chemokines and role in pathology

Chemokines are low molecular mass chemotactic proteins that signal through G protein-coupled receptors (GPCR). Chemokine activity is regulated at multiple levels including posttranslational modification (PTM). Proteolytic processing of chemokines at the NH2-terminus by metalloproteases and serine proteases has been reported to severely affect chemokine activity. In addition, COOH-terminal truncation and glycosylation has been detected on some chemokines. Recently, the inflammatory chemokines CXCL8 and CXCL10 were observed in deiminated or citrullinated forms. Citrullination of CXC chemokines significantly reduces their inflammatory activity. Peptidylarginine deiminases (PAD) are the enzymes converting peptidylarginine into peptidylcitrulline. The human PAD family consists of five distinct members with a specific tissue distribution and substrate specificity. PAD regulates the biological function of different proteins by citrullination. Therefore, PAD plays an important role in homeostatic processes such as the development of hair, skin, the myelin sheath and embryogenesis as well as in gene transcription. PAD also has a key role in inflammation as it is essential for the formation of neutrophil extracellular traps (NETs) and citrullinates chemokines. PAD misexpression, however, may be involved in the development of several diseases such as cancer and auto-immune diseases including rheumatoid arthritis and multiple sclerosis. Therefore, PAD is suggested to be a potential new drug target.