title: ATP induces protein arginine deiminase 2-dependent citrullination in mast cells through the P2X7 purinergic receptor.
abstract: Posttranslational modifications regulate physiology either by directly modulating protein function or by impacting immune recognition of self-proteins. Citrullination is a posttranslational modification formed by the conversion of arginine residues into the citrulline amino acid by protein arginine deiminase (PAD) family members. We have identified mast cells as a major source of the PAD2 enzyme. Activation of the P2X7 purinergic receptor (P2X7) by the inflammatory "danger" signal ATP induces PAD2 activity and robust protein citrullination. P2X7-mediated activation of PAD2 is sensitive to p38 MAPK and protein kinase C inhibitors, and PAD2 regulates the expression of the TNFR2, Adamts-9, and Rab6b transcripts in mast cells. Further, the PAD2 enzyme and its citrullinated substrate proteins are released from mast cells on activation with ATP. PAD2 expression is closely linked with inflammation in rheumatoid arthritis (RA) synovial tissue, and PAD2 and citrullinated proteins are found in the synovial fluid of RA patients. In addition, RA is associated with the development of autoantibodies to citrullinated self-proteins. Our results suggest that P2X7 activation of mast cells may play a role in inflammation by providing PAD2 and PAD2 substrates access to the extracellular space.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92093, USA.
authors.forename: Sanja
authors.initials: S
authors.lastname: Arandjelovic
authors.forename: Katherine R
authors.initials: KR
authors.lastname: McKenney
authors.forename: Sunamita S
authors.initials: SS
authors.lastname: Leming
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Mowen
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism*; D005110:Extracellular Space / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D058486:Receptors, Purinergic P2X7; D002956:Citrulline; D000255:Adenosine Triphosphate; D011484:Protein-Arginine N-Methyltransferases; C464934:protein arginine methyltransferase 2