title: Inactivation of α1-proteinase inhibitor by Candida albicans aspartic proteases favors the epithelial and endothelial cell colonization in the presence of neutrophil extracellular traps.
abstract: Candida albicans, a causative agent of opportunistic fungal infections in immunocompromised patients, uses ten secreted aspartic proteases (SAPs) to deregulate the homeostasis of the host organism on many levels. One of these deregulation mechanisms involves a SAP-dependent disturbance of the control over proteolytic enzymes of the host by a system of dedicated proteinase inhibitors, with one important example being the neutrophil elastase and alpha1-proteinase inhibitor (A1PI). In this study, we found that soluble SAPs 1-4 and the cell membrane-anchored SAP9 efficiently cleaved A1PI, with the major cleavage points located at the C-terminal part of A1PI in a close vicinity to the reactive-site loop that plays a critical role in the inhibition mechanism. Elastase is released by neutrophils to the environment during fungal infection through two major processes, a degranulation or formation of neutrophil extracellular traps (NET). Both, free and NET-embedded elastase forms, were found to be controlled by A1PI. A local acidosis, resulting from the neutrophil activity at the infection sites, favors A1PI degradation by SAPs. The deregulation of NET-connected elastase affected a NET-dependent damage of epithelial and endothelial cells, resulting in the increased susceptibility of these host cells to candidal colonization. Moreover, the SAP-catalyzed cleavage of A1PI was found to decrease its binding affinity to a proinflammatory cytokine, interleukin-8. The findings presented here suggest a novel strategy used by C. albicans for the colonization of host tissues and overcoming the host defense.
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Gogol
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Ostrowska
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Klaga
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Bochenska
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Wolak
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Aoki
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kozik
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Rapala-Kozik
mesh_terms: D000595:Amino Acid Sequence; D057055:Aspartic Acid Proteases / Q000378:metabolism*; D002176:Candida albicans / Q000201:enzymology*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D009504:Neutrophils; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000187:drug effects*
chemical_list: D000515:alpha 1-Antitrypsin; D057055:Aspartic Acid Proteases