KRE5Gene Null Mutant Strains ofCandida albicansAre Avirulent and Have Altered Cell Wall Composition and Hypha Formation Properties

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Abstract
The UDP-glucose:glycoprotein glucosyltransferase (UGGT) is an endoplasmic reticulum sensor for quality control of glycoprotein folding.Saccharomyces cerevisiaeis the only eukaryotic organism so far described lacking UGGT-mediated transient reglucosylation of N-linked oligosaccharides. The only gene inS. cerevisiaewith similarity to those encoding UGGTs isKRE5. S. cerevisiae KRE5deletion strains show severely reduced levels of cell wall β-1,6-glucan polymer, aberrant morphology, and extremely compromised growth or lethality, depending on the strain background. Deletion of both alleles of theCandida albicans KRE5gene gives rise to viable cells that are larger than those of the wild type (WT), tend to aggregate, have enlarged vacuoles, and show major cell wall defects.C. albicans kre5/kre5mutants have significantly reduced levels of β-1,6-glucan and more chitin and β-1,3-glucan and less mannoprotein than the WT. The remaining β-1,6-glucan, about 20% of WT levels, exhibits a β-1,6-endoglucanase digestion pattern, including a branch point-to-linear stretch ratio identical to that of WT strains, suggesting that Kre5p is not a β-1,6-glucan synthase.C. albicans KRE5is a functional homologue ofS. cerevisiae KRE5; it partially complements both the growth defect and reduced cell wall β-1,6-glucan content ofS. cerevisiae kre5viable mutants.C. albicans kre5/kre5homozygous mutant strains are unable to form hyphae in several solid and liquid media, even in the presence of serum, a potent inducer of the dimorphic transition. Surprisingly the mutants do form hyphae in the presence ofN-acetylglucosamine. Finally,C. albicans KRE5homozygous mutant strains exhibit a 50% reduction in adhesion to human epithelial cells and are completely avirulent in a mouse model of systemic infection.

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