Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92093, USA.
J Immunol. 2012 Oct 15;189(8):4112-22. doi: 10.4049/jimmunol.1201098. Epub 2012 Sep 14.
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.
翻译后修饰通过直接调节蛋白质功能或影响自身蛋白质的免疫识别来调节生理功能。瓜氨酸化是一种翻译后修饰，由蛋白质精氨酸脱氨酶（PAD）家族成员将精氨酸残基转化为瓜氨酸氨基酸形成。我们已确定肥大细胞是PAD2酶的主要来源。炎症“危险”信号ATP激活P2X7嘌呤能受体（P2X7）可诱导PAD2活性和强大的蛋白质瓜氨酸化。P2X7介导的PAD2激活对p38丝裂原活化蛋白激酶和蛋白激酶C抑制剂敏感，并且PAD2调节肥大细胞中TNFR2、Adamts-9和Rab6b转录本的表达。此外，用ATP激活时，PAD2酶及其瓜氨酸化底物蛋白会从肥大细胞中释放出来。PAD2表达与类风湿性关节炎（RA）滑膜组织中的炎症密切相关，并且在RA患者的滑液中发现了PAD2和瓜氨酸化蛋白。此外，RA与针对瓜氨酸化自身蛋白的自身抗体的产生有关。我们的结果表明，肥大细胞的P2X7激活可能通过使PAD2和PAD2底物进入细胞外空间而在炎症中发挥作用。
