Distinct Ire1-driven transcriptional responses control morphogenesis in Candida albicans

The pathogenic yeast Candida albicans relies on morphogenesis—the transition from spherical yeast to filamentous hyphal forms—for infection. While morphogenesis requires Ire1, a transmembrane protein that canonically initiates the Unfolded Protein Response (UPR) through HAC1 mRNA splicing, the specific mechanisms linking Ire1 to filamentation remain unclear. Using transcriptome analysis, we found that the Ire1-dependent transcriptional response driving morphogenesis is fundamentally distinct from the canonical UPR response to proteotoxic stress, with minimal overlap between programs. Remarkably, morphogenesis occurs without detectable HAC1 splicing, and HAC1 deletion only partially impairs filamentation, unlike complete loss with IRE1 deletion. These findings establish that Ire1 regulates hyphal development through previously uncharacterized HAC1 -independent pathways. Our data reveal decreased transcription of secretory proteins in an Ire1-dependent manner, providing compelling evidence that C. albicans possesses regulated Ire1-dependent decay (RIDD) activity—a post-transcriptional mechanism not previously characterized in this pathogen. Additionally, we identify cell wall integrity as a key HAC1 -independent mechanism, with Ire1—but not Hac1—essential for cell wall stress tolerance and upregulation of cell wall biosynthesis genes during filamentation. Given Ire1’s essential role in pathogenesis and extensive development of Ire1-targeting compounds for mammalian systems, our findings position Ire1 as a highly promising druggable target for novel antifungal therapeutics and development of fungal-specific inhibitors.