title: Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium.
abstract: A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Regn
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Laggerbauer
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jentzsch
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Deepak
authors.initials: D
authors.lastname: Ramanujam
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ahles
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sichler
authors.affiliation: Institute of Pathology, Helmholtz Center Munich, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider Straße 2, 97080 Würzburg, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider Straße 2, 97080 Würzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, 80802 Munich, Germany. Electronic address: stefan.engelhardt@tum.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D056657:Cathepsin K / Q000378:metabolism; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism*; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C486456:CMKLR1 protein, mouse; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C523686:chemerin protein, mouse; C524777:protease inhibitor 16, mouse; D056657:Cathepsin K
keywords: Chemerin; Chemerin processing; Peptidase inhibitor 16 (PI16); Protease inhibition; RARRES2; TIG2