Differential requirement for the Ire1 luminal and transmembrane domains in Candida albicans drug resistance and pathogenicity

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 methods deploy divergent transcriptional programs.

Whether these activation modes are functionally 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 (ire1ΔLD), rendering the sensor responsive to LBS but unable to detect proteotoxic stress. The ire1ΔLD strain tolerated membrane stress induced by the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock and cell wall stress.