title: Role of neutrophil proteinase 3 and mast cell chymase in chemerin proteolytic regulation.
abstract: Chemerin is a potent chemotactic factor that was identified recently as the ligand of ChemR23, a G protein-coupled receptor expressed by mononuclear phagocytes, dendritic cells (DCs), and NK cells. Chemerin is synthesized as a secreted precursor, prochemerin, which is poorly active on ChemR23. However, prochemerin can be converted rapidly into a full ChemR23 agonist by proteolytic removal of a carboxy-terminal peptide. This maturation step is mediated by the neutrophil-derived serine proteases elastase and cathepsin G. In the present work, we have investigated proteolytic events that negatively control chemerin activity. We demonstrate here that neutrophil-derived proteinase 3 (PR3) and mast cell (MC) chymase are involved in the generation of specific chemerin variants, which are inactive, as they do not induce calcium release or DC chemotaxis. Mass spectrometry analysis showed that PR3 specifically converts prochemerin into a chemerin form, lacking the last eight carboxy-terminal amino acids, and is inactive on ChemR23. Whereas PR3 had no effect on bioactive chemerin, MC chymase was shown to abolish chemerin activity by the removal of additional amino acids from its C-terminus. This effect was shown to be specific to bioactive chemerin (chemerin-157 and to a lesser extent, chemerin-156), as MC chymase does not use prochemerin as a substrate. These mechanisms, leading to the production of inactive variants of chemerin, starting from the precursor or the active variants, highlight the complex interplay of proteases regulating the bioactivity of this novel mediator during early innate immune responses.
authors.affiliation: Institute of Interdisciplinary Research in Human and Molecular Biology, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium.
authors.forename: Aude
authors.initials: A
authors.lastname: Guillabert
authors.forename: Valérie
authors.initials: V
authors.lastname: Wittamer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bondue
authors.forename: Véronique
authors.initials: V
authors.lastname: Godot
authors.forename: Virginie
authors.initials: V
authors.lastname: Imbault
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
authors.forename: David
authors.initials: D
authors.lastname: Communi