Dac6 affects thermotolerance and pathogenicity of Cryptococcus neoformans by modulating utilization of host infection-related amino acids

Thermotolerance of fungal pathogens is critical for host adaptation, and most fungi cannot survive at mammalian body temperatures, making heat stress a key host defense. Cryptococcus neoformans, a leading cause of fungal meningitis, must overcome host fever and nutrient limitation to establish infection. However, the metabolic adaptations enabling C. neoformans to overcome this barrier remain unclear. Here, we investigated the role of a protein deacetylase Dac6 in C. neoformans thermotolerance and pathogenicity, focusing on its metabolic regulation under heat stress. We found that Dac6 is a thermotolerance regulator, distinct from its yeast homolog Rpd3, and its expression correlates with heat resistance in clinical strains. Multi-omics analyses reveal that Dac6 modulates histone acetylation and gene expression to reprogram amino acid metabolism under heat stress, particularly lysine and threonine. Notably, lysine and threonine are also the major altered metabolites in host during cryptococcal infection, and Dac6 deletion impaired fungal utilization of lysine and threonine under heat stress in vitro and in vivo. Consequently, Dac6 deficiency leads to reduced lung and brain colonization, and attenuated virulence in mice. Our study uncovers a metabolic adaptation mechanism by which Dac6 links nutrient utilization to thermotolerance and virulence, providing new insights into fungal survival strategies in high-temperature host environments. Overall design: For Cryptococcus neoformans, performed paired-end RNA-seq of fungal strains in 100ml YPD broth at OD600=1 at 30°C or 39°C, respectively in biological triplicates. For Saccharomyces cerevisiae, performed paired-end RNA-seq of fungal strains in 100ml YPD broth at OD600=1 at 39°C, respectively in biological triplicates.