Abstract
Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 is expressed in granulocytes and is essential for the formation of neutrophil extracellular traps (NETs) via PAD4-mediated histone citrullination. Citrullination of histones is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA that is coated with antimicrobial molecules. Numerous stimuli have been reported to lead to PAD4 activation and NET formation. However, how this signaling process proceeds and how PAD4 becomes activated in cells is largely unknown. Herein, we describe the various stimuli and signaling pathways that have been implicated in PAD4 activation and NET formation, including the role of reactive oxygen species generation. To provide a foundation for the above discussion, we first describe PAD4 structure and function, and how these studies led to the development of PAD-specific inhibitors. A comprehensive survey of the receptors and signaling pathways that regulate PAD4 activation will be important for our understanding of innate immunity, and the identification of signaling intermediates in PAD4 activation may also lead to the generation of pharmaceuticals to target NET-related pathogenesis.
Highlights
THE PEPTIDYL ARGININE DEIMINASE FAMILY The mammalian genome encodes 20 natural amino acids; this diversity is greatly increased by posttranslational modification of the original set to yield more than one hundred unique amino acids (Uy and Wold, 1977)
Since H2O2 treatment can activate PAD4-mediated histone deimination in primary murine and human neutrophils (Neeli et al, 2008; Li et al, 2010), and since NADPH activation seems to be upstream of neutrophil extracellular traps (NETs) formation (Neeli et al, 2009), we speculate that PAD4 activation may be downstream of NADPH (Figure 3)
Neutrophil extracellular traps have been reported in several pathological scenarios, including systemic lupus erythematosus (SLE), sepsis, thrombosis, and infectious disease, and may induce or exacerbate inflammation through prolonged inflammatory response, tissue damage, and presentation of neo-antigens
Summary
THE PEPTIDYL ARGININE DEIMINASE FAMILY The mammalian genome encodes 20 natural amino acids; this diversity is greatly increased by posttranslational modification of the original set to yield more than one hundred unique amino acids (Uy and Wold, 1977). This calcium-induced formation of the active site is unique to the PADs, and represents a novel mechanism of enzyme activation (Arita et al, 2004). Histone citrullination is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA coated with antimicrobial molecules (Neeli et al, 2008; Wang et al, 2009; Li et al, 2010).
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