Bader, O. and Schaller, M. and Klein, S. and Kukula, J. and Haack, K. and Muhlschlegel, F.A. and Korting, H.C. and Schafer, W. and Hube, B. (2001) The KEX2 Gene of Candida Glabrata is required for Cell Surface Integrity. Molecular Microbiology, 41 (6). pp. 1431-1444. ISSN 0950-382X.
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Candida glabrata has emerged as one of the most common causes of candidosis. In order to identify factors that are necessary for viability and pathogenicity of this fungal pathogen, we analysed the role of the KEX2 gene, which codes for a regulatory endoproteinase that is known to process certain virulence factors in Candida albicans. The KEX2 gene from C. glabrata was cloned and found to have 51% and 62% identity and high structural similarities to the homologous counterparts in C. albicans and Saccharomyces cerevisiae. KEX2 was expressed at all time points investigated during growth in complex medium. In order to investigate the role of this putative regulatory proteinase, Kex2-deficient mutants were produced. In addition to known kex2 phenotypes, such as pH and calcium hypersensitivity, the mutants grew in cellular aggregates and were found to be hypersensitive to several antifungal drugs that target the cell membrane, including azoles, amorolfine and amphotericin B. Ultrastructural investigation after exposure to low doses of itraconazole showed azole-specific alterations such as enlarged vacuoles and proliferation of the cytoplasmatic membrane in the kex2 mutants, but not in the control strains. In contrast, antifungals such as 5-flucytosine and hydroxypyridones inhibited growth of the kex2 mutants and the control strains to the same extent. In an in vitro model of oral candidosis, kex2 mutants showed reduced tissue damage in the presence of itraconazole compared with the control infections. These data suggest that Kex2 is involved in the processing of proteins that are essential for cell surface integrity of C. glabrata.
|Additional information:||0950-382X (Print) In Vitro Journal Article Research Support, Non-U.S. Gov't|
|Uncontrolled keywords:||Amino Acid Sequence Antifungal Agents/pharmacology Azoles/pharmacology Base Sequence Candida/drug effects/*enzymology/*genetics/pathogenicity Candidiasis, Oral/drug therapy/microbiology Cell Division/drug effects Cell Membrane/enzymology Cloning, Molecular DNA Primers/genetics Drug Resistance, Fungal/genetics Fungal Proteins/genetics/metabolism *Genes, Fungal Humans Molecular Sequence Data Mutation *Proprotein Convertases *Saccharomyces cerevisiae Proteins Sequence Homology, Amino Acid Substrate Specificity Subtilisins/*genetics/*physiology Virulence/genetics|
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences > Biomedical Research Group|
|Depositing User:||F.A. Muhlschlegel|
|Date Deposited:||28 Oct 2008 19:01|
|Last Modified:||28 Mar 2012 10:44|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/6188 (The current URI for this page, for reference purposes)|
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