Journal Article

<i>Cryptococcus neoformans</i> Yop1, an endoplasmic reticulum curvature-stabilizing protein, participates with Sey1 in influencing fluconazole-induced disomy formation

Popchai Ngamskulrungroj, Yun Chang, Bryan Hansen, Cliff Bugge, Elizabeth Fischer and Kyung J. Kwon-Chung

in FEMS Yeast Research

Volume 12, issue 7, pages 748-754
Published in print November 2012 |
Published online October 2012 | e-ISSN: 1567-1364 | DOI: http://dx.doi.org/10.1111/j.1567-1364.2012.00824.x

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Cryptococcus neoformans, an opportunistic fungal pathogen, manifests an intrinsic adaptive mechanism of resistance toward fluconazole (FLC) termed heteroresistance. Heteroresistance is characterized by the emergence of minor resistant subpopulations at levels of FLC that are higher than the strain's minimum inhibitory concentration. The heteroresistant clones that tolerate high concentrations of FLC often contain disomic chromosome 4 (Chr4). SEY1, GLO3, and GCS2 on Chr4 are responsible for endoplasmic reticulum (ER) integrity and important for Chr4 disomy formation under FLC stress. We sought an evidence of a direct relationship between ER morphology and Chr4 disomy formation. Deletion of the YOP1 gene on Chr7, which encodes an ER curvature-stabilizing protein that interacts with Sey1, perturbed ER morphology without affecting FLC susceptibility or the frequency of FLC-induced disomies. However, deletion of both YOP1 and SEY1, not only perturbed ER morphology more severely than in sey1Δ or yop1Δ strains, but also abrogated the FLC-induced disomy. Although the heteroresistance phenotype was retained in the sey1Δyop1Δ strains, tolerance to FLC appeared to have resulted not from chromosome duplication but from gene amplification restricted to the region surrounding ERG11 on Chr1. These data support the importance of ER integrity in C. neoformans for the formation of disomy under FLC stress.

Keywords: Cryptococcus neoformans; disomy formation; fluconazole; antifungal resistance; heteroresistance; endoplasmic reticulum

Journal Article.  3963 words.  Illustrated.

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