Nd Bioinformatics, and Analytical Biochemistry, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krak , Poland, the Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Study, Jagiellonian University, 30-387 Krak , Poland, and the Palo Alto Veterans Institute for Analysis, Veterans Affairs Palo Alto Well being Care System, Palo Alto, CaliforniaEdited by Chris WhitfieldChemerin is actually a leukocyte attractant, adipokine, and antimicrobial protein abundantly made in the skin epidermis. Despite the fact that the majority of the bactericidal activity present in human skin exudates is chemerin-dependent, just how chemerin shapes skin defenses remains obscure. Here we demonstrate that p4, a potent antimicrobial human chemerin peptide derivative, displays killing activity against pathogenic methicillin-resistant Staphylococcus aureus strains and suppresses microbial development in a topical skin infection model. Mechanistically, we show that p4 homodimerization is needed for maximal bactericidal activity and that an oxidative atmosphere, like in the skin surface, facilitates p4 disulfide bridge formation, required for the dimerization. p4 led to fast damage from the bacterial internal membrane and inhibited the interaction between the membranous cytochrome bc1 complicated and its redox partner, cytochrome c. These benefits suggest that a chemerin p4 primarily based defense tactic combats bacterial challenges in the skin surface.Chemerin is a natural ligand for the metabotropic receptor CMKLR1 having a increasing variety of biological functions. Chemerin is best known as a chemotactic factor involved in controlling homing of distinct (CMKLR1) PDGF-DD Proteins site immune cells, which include dendritic cells or macrophages, to web sites of inflammation (1). Chemerin also plays a crucial role in other physiological processes, which include the regulation of metabolism, either by influencing the differentiation of fat cells or controlling the production and secretion of insulin by pancreatic cells (four, 5). Furthermore, chemerin has been implicated in angiogenesis and regulation of vascular function (six, 7). Chemerin is synthesized as an inactive precursor (prochemerin) that circulates within the bloodstream. Upon proteolytic cleavage of its C terminus, prochemerin is converted into a potent agonist of CMKLR1. The sequence on the chemerin C terminus is essential forThis work was supported by Polish National Science Center Grant UMO 2014/ 12/W/NZ6/00454 (to J. C., E. P., and B. A. Z.). The authors declare that they have no conflicts of interest together with the contents of this article. This IP-10/CXCL10 Proteins Biological Activity article consists of Figs. S1 and S2 and supporting text. 1 To whom correspondence must be addressed: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7 St., 30-387 Krakow, Poland. E-mail: [email protected] activity. Enzymes that activate chemerin incorporate cysteine and serine proteases involved within the blood coagulation cascade and inflammatory processes (eight 0). Chemerin is expressed by numerous types of epithelial cells (113) and, in skin keratinocytes, is up-regulated in response to bacteria and acute-phase cytokines (14). Recombinant chemerin and chemerin-derived peptide four (p4), situated inside a central area in the chemerin protein sequence, are each active against a broad array of microorganisms, like skin-, lung-, and oral cavityassociated bacteria also because the fungal pathogen Candida albicans (8, 15, 16). Inhibition of.