Du Xiao-Yan, Zabel Brian A, Myles Timothy, Allen Samantha J, Handel Tracy M, Lee Peter P, Butcher Eugene C, Leung Lawrence L
Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.
J Biol Chem. 2009 Jan 9;284(2):751-8. doi: 10.1074/jbc.M805000200. Epub 2008 Nov 14.
Chemerin is a potent chemoattractant for cells expressing the serpentine receptor CMKLR1 (chemokine-like receptor 1), such as plasmacytoid dendritic cells and tissue macrophages. The bioactivity of chemerin is post-translationally regulated; the attractant circulates in blood in a relatively inactive form (prochemerin) and is activated by carboxyl-terminal proteolytic cleavage. We discovered that plasma carboxypeptidase N (CPN) and B (CPB or activated thrombin-activable fibrinolysis inhibitor, TAFIa) enhanced the bioactivity of 10-mer chemerin peptide NH(2)-YFPGQFAFSK-COOH by removing the carboxyl-terminal lysine (K). Sequential cleavages of either a prochemerin peptide (NH(2)-YFPGQFAFSKALPRS-COOH) or recombinant full-length prochemerin by plasmin and CPN/CPB substantially increased their chemotactic activities. Endogenous CPN present in circulating plasma enhanced the activity of plasmin-cleaved prochemerin. In addition, we discovered that platelets store chemerin protein and release it upon stimulation. Thus circulating CPN/CPB and platelets may potentially contribute to regulating the bioactivity of leukocyte chemoattractant chemerin, and further extend the molecular link between blood coagulation/fibrinolysis and CMKLR1-mediated immune responses.
瑞托蛋白是一种对表达蛇形受体CMKLR1（趋化因子样受体1）的细胞具有强大趋化作用的趋化因子，这些细胞包括浆细胞样树突状细胞和组织巨噬细胞。瑞托蛋白的生物活性在翻译后受到调控；这种趋化因子以相对无活性的形式（前瑞托蛋白）在血液中循环，并通过羧基末端的蛋白水解切割而被激活。我们发现血浆羧肽酶N（CPN）和B（CPB或活化的凝血酶激活的纤溶抑制物，TAFIa）通过去除羧基末端的赖氨酸（K）增强了10肽瑞托蛋白NH(2)-YFPGQFAFSK-COOH的生物活性。纤溶酶和CPN/CPB对前瑞托蛋白肽（NH(2)-YFPGQFAFSKALPRS-COOH）或重组全长前瑞托蛋白的顺序切割显著增加了它们的趋化活性。循环血浆中存在的内源性CPN增强了纤溶酶切割的前瑞托蛋白的活性。此外，我们发现血小板储存瑞托蛋白并在受到刺激时释放它。因此，循环中的CPN/CPB和血小板可能有助于调节白细胞趋化因子瑞托蛋白的生物活性，并进一步扩展凝血/纤溶与CMKLR1介导的免疫反应之间的分子联系。
