<i>Candida albicans</i> -induced ubiquitination of EGFR reveals novel host–fungal interaction pathways

<i>Candida albicans</i> 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 <i>ECE1</i> gene, induces receptor signaling and immune responses. While EGFR ubiquitination critically regulates receptor trafficking and signaling, its involvement during <i>C. albicans</i> infection has remained unexplored. Here, we demonstrate that <i>C. albicans</i> induces EGFR ubiquitination, leading to altered trafficking and lysosomal degradation in an <i>ECE1</i>- and <i>ALS3</i>-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 <i>C. albicans</i> and <i>ece1</i>Δ/Δ and <i>als3</i>Δ/Δ mutant strains were found to differentially regulate <i>Egfr</i> expression, ubiquitin pathway-associated genes, and protein ubiquitination. Furthermore, conditional EGFR knockout was protective during infection. Together, our findings reveal that <i>C. albicans</i> infection modulates the host ubiquitin system, including direct effects on EGFR, highlighting a novel aspect of host-fungal interactions.IMPORTANCE<i>Candida albicans</i> 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 <i>C. albicans</i> 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 <i>C. albicans</i> manipulates protein ubiquitination and regulation in epithelial cells, offering new insights into fungal pathogenesis and potential therapeutic approaches that target host pathways.