Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion

The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. a...

Full description

Bibliographic Details
Main Authors:	Citiulo, Francesco, Jacobsen, Ilse D., Miramón, Pedro, Schild, Lydia, Brunke, Sascha, Zipfel, Peter, Brock, Matthias, Hube, Bernhard, Wilson, Duncan
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386192/

id	pubmed-3386192
recordtype	oai_dc
spelling	pubmed-33861922012-07-03 Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion Citiulo, Francesco Jacobsen, Ilse D. Miramón, Pedro Schild, Lydia Brunke, Sascha Zipfel, Peter Brock, Matthias Hube, Bernhard Wilson, Duncan Research Article The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution. Public Library of Science 2012-06-28 /pmc/articles/PMC3386192/ /pubmed/22761575 http://dx.doi.org/10.1371/journal.ppat.1002777 Text en Citiulo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Citiulo, Francesco Jacobsen, Ilse D. Miramón, Pedro Schild, Lydia Brunke, Sascha Zipfel, Peter Brock, Matthias Hube, Bernhard Wilson, Duncan
spellingShingle	Citiulo, Francesco Jacobsen, Ilse D. Miramón, Pedro Schild, Lydia Brunke, Sascha Zipfel, Peter Brock, Matthias Hube, Bernhard Wilson, Duncan Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
author_facet	Citiulo, Francesco Jacobsen, Ilse D. Miramón, Pedro Schild, Lydia Brunke, Sascha Zipfel, Peter Brock, Matthias Hube, Bernhard Wilson, Duncan
author_sort	Citiulo, Francesco
title	Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_short	Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_full	Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_fullStr	Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_full_unstemmed	Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion
title_sort	candida albicans scavenges host zinc via pra1 during endothelial invasion
description	The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386192/
_version_	1611540020935524352

Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion

Similar Items