Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium. (October 2016)

• Record Type: Journal Article
• Authors: Regn, Michael; Laggerbauer, Bernhard; Jentzsch, Claudia; Ramanujam, Deepak; Ahles, Andrea; Sichler, Sonja; Calzada-Wack, Julia; Koenen, Rory R.; Braun, Attila; Nieswandt, Bernhard; Engelhardt, Stefan
• Is Part Of: Journal of molecular and cellular cardiology. Volume 99(2016:Oct.)
• Page Start: 57
• Page End: 64
• Publication Date: 2016-10
• Subjects: Peptidase inhibitor 16 (PI16) -- Chemerin -- RARRES2 -- TIG2 -- Protease inhibition -- Chemerin processing; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.08.010
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: First evidence for the function of peptidase inhibitor 16 PI16 suppresses proteolytic activation of the chemokine chemerin. Generation of globally PI16-deficient mice using a floxed-PI16 allele.