Regulation of chemerin bioactivity by plasma carboxypeptidase N, carboxypeptidase B (activated thrombin-activable fibrinolysis inhibitor), and platelets.
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.
Du
Xiao-Yan
XY
Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Zabel
Brian A
BA
Myles
Timothy
T
Allen
Samantha J
SJ
Handel
Tracy M
TM
Lee
Peter P
PP
Butcher
Eugene C
EC
Leung
Lawrence L
LL
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D043424:Carboxypeptidase B / Q000378:metabolism*; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D005342:Fibrinolysis; D006801:Humans; D006868:Hydrolysis; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D001121:Lysine Carboxypeptidase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015539:Platelet Activation; D011499:Protein Processing, Post-Translational; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation
D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D043424:Carboxypeptidase B; D001121:Lysine Carboxypeptidase; D013917:Thrombin