Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity
- 1Western University
Abstract
The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.
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BibTeX
@misc{stackcouture2026differential,
title = {{Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity}},
author = {S. Stack-Couture and N. Towriss and I. Skulska and A. Kalabina and J. Genereaux and V. Dumeaux and R. S. Shapiro and P. Lajoie},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753484},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753484v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity
AU - S. Stack-Couture
AU - N. Towriss
AU - I. Skulska
AU - A. Kalabina
AU - J. Genereaux
AU - V. Dumeaux
AU - R. S. Shapiro
AU - P. Lajoie
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753484
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753484v1
AB - The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.
ER -