p24 family proteins are critical for cell wall integrity, protein secretion, and virulence in <i>Candida albicans</i>

<i>Candida albicans</i> is a fungal commensal and also a prevalent pathogen of humans. p24 proteins are a family of type I membrane proteins regarded as cargo receptors for endoplasmic reticulum (ER) to Golgi transport and are thought to be involved in regulating secretion. Here, we sought to explore the impact of this family of proteins on <i>C. albicans</i> pathogenicity. The expression of all four members of the p24 family is upregulated during invasive candidiasis. Their expression is independent of yeast-to-hypha transition but is highly induced by tissue culture conditions. We then generated single deletion mutants for each member of the p24 family for phenotypic characterization. All these mutants exhibit significantly attenuated virulence in a mouse model of systemic infection and reduced survival in macrophages but are dispensable for vegetative growth and morphogenesis. They also show lower abundance of chitin and phosphomannan in the cell wall and enhanced sensitivity to fluconazole, an azole antifungal drug. Importantly, the absence of p24 proteins leads to defective protein secretion in <i>C. albicans</i>, including pathogenicity-related effectors and lipases, and reduces commensal fitness. These results suggest that p24 proteins are critical for cell wall integrity, secretion of virulence factors, and virulence in <i>C. albicans</i>.IMPORTANCE<i>Candida albicans</i> is an important opportunistic fungal pathogen of immunocompromised individuals and a top-ranking WHO fungal priority pathogen due to the high frequency and mortality of invasive candidiasis. The eukaryotic p24 family of proteins has long been known to be key regulators of protein trafficking along the secretory pathway, but their potential roles regarding pathogenesis in <i>C. albicans</i> remain unknown. Here, we discover that all members of the p24 family are required for cell wall integrity, proper secretion of virulence factors, survival in macrophages, and virulence in a systemic infection model. However, they are dispensable for vegetative growth and yeast-to-hypha transition, the best-known virulence attribute. Our study systematically investigates <i>C. albicans</i> p24 proteins and highlights the critical role that the early secretory pathway plays in fungal pathogenicity.