Cryptococcus neoformans   Yop1 , an endoplasmic reticulum curvature-stabilizing protein, participates with  Sey1  in influencing fluconazole-induced disomy formation.
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 sey1∆ or yop1∆ strains, but also abrogated the FLC-induced disomy. Although the heteroresistance phenotype was retained in the sey1∆yop1∆ 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.
Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
Popchai
P
Ngamskulrungroj
Yun
Y
Chang
Bryan
B
Hansen
Cliff
C
Bugge
Elizabeth
E
Fischer
Kyung J
KJ
Kwon-Chung
D000782:Aneuploidy; D000935:Antifungal Agents / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D025141:Drug Resistance, Fungal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D017353:Gene Deletion
D000935:Antifungal Agents; D005656:Fungal Proteins; D015725:Fluconazole