Candida albicans-induced ubiquitination of EGFR reveals novel host-fungal interaction pathways

Candida albicans causes severe mucosal and systemic infections, with hypha formation playing a key role in its virulence. Hyphal invasion via endocytosis is mediated predominantly through interactions between Als3p and the epidermal growth factor receptor (EGFR). Subsequent EGFR activation by candidalysin, a hyphal-secreted cytolytic peptide toxin encoded by the ECE1 gene, induces receptor signaling and immune responses. While EGFR ubiquitination critically regulates receptor trafficking and signaling, its involvement during C. albicans infection has remained unexplored. Here, we demonstrate that C. albicans induces EGFR ubiquitination, leading to altered trafficking and lysosomal degradation in an ECE1- and ALS3-dependent manner. This correlates with changes in EGFR ligand expression, adaptor recruitment, and protein ubiquitination in oral epithelial cells. In a mouse model of oropharyngeal candidiasis, wild-type C. albicans and ece1Δ/Δ and als3Δ/Δ mutant strains were found to differentially regulate Egfr expression, ubiquitin pathway-associated genes, and protein ubiquitination. Furthermore, conditional EGFR knockout was protective during infection. Together, our findings reveal that C. albicans infection modulates the host ubiquitin system, including direct effects on EGFR, highlighting a novel aspect of host-fungal interactions.IMPORTANCECandida albicans is a common fungal pathogen that causes both mucosal infections, such as thrush, and life-threatening systemic diseases. A key step in infection is the fungus invading epithelial tissues and activating the host epidermal growth factor receptor (EGFR). We discovered that C. albicans alters how EGFR is regulated by inducing its ubiquitination, a modification that leads to receptor degradation. This process depends on two major fungal virulence factors: the adhesin Als3p and Ece1p, the polypeptide that contains the candidalysin toxin. The fungus also broadly increases protein ubiquitination in oral epithelial cells. In a mouse model of oral infection, loss of EGFR in epithelial tissues reduced disease severity, suggesting that the receptor helps the fungus establish infection. These findings reveal a previously unrecognized strategy by which C. albicans manipulates protein ubiquitination and regulation in epithelial cells, offering new insights into fungal pathogenesis and potential therapeutic approaches that target host pathways.