The very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase Phs1 regulates ATP levels and virulence in Cryptococcus neoformans

Cryptococcus neoformans is a significant fungal pathogen that poses a serious threat to immunocompromised individuals, particularly those with HIV/AIDS. In the study, we found that the very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase, Phs1, was important for melanin formation, growth at 39 °C, maintenance of cell wall integrity, and virulence in murine models. Through RNA sequencing, we examined transcriptomic alterations and discovered that the deletion of PHS1 resulted in the upregulation of 169 genes and downregulation of 540 genes, many of which are associated with critical metabolic and cellular functions. Notably, the PHS1-deficient mutant exhibited a significant reduction in ATP-dependent activities compared to wild-type cells at mRNA level. Furthermore, metabolomic data indicated considerable disruptions in oxidative phosphorylation and the TCA cycle following PHS1 deletion. Collectively, our findings underscore the potential role of Phs1 in cellular energy regulation and its contribution to the virulence of C. neoformans.