Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium

J Mol Cell Cardiol. 2016 Oct;99:57-64. doi: 10.1016/j.yjmcc.2016.08.010. Epub 2016 Aug 15.

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.

Keywords: Chemerin; Chemerin processing; Peptidase inhibitor 16 (PI16); Protease inhibition; RARRES2; TIG2.

MeSH terms

  • Animals
  • Cathepsin K / metabolism
  • Cell Communication
  • Cell Membrane / metabolism
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Fibroblasts / metabolism
  • Gene Knockout Techniques
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Myocardium / metabolism*
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction

Substances

  • CMKLR1 protein, mouse
  • Chemokines
  • Intercellular Signaling Peptides and Proteins
  • Proteinase Inhibitory Proteins, Secretory
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • chemerin protein, mouse
  • protease inhibitor 16, mouse
  • Cathepsin K