ChIP-seq of Cryptococcus neoformans Dac6-FLAG under heat stress (PRJCA050491)
Thermotolerance is critical for fungal survival in host, but the mechanism of metabolic remodeling that allows pathogenic fungi such as Cryptococcus neoformans to survive heat stress is not known. Here, we investigated a protein deacetylase Dac6 is a thermotolerance regulator in C. neoformans, distinct from its yeast homolog Rpd3, and its expression correlates with heat resistance in clinical strains. Integrated multi-omics analyses revealed that Dac6 alters histone acetylation and gene expression to reprogram amino acid metabolism under heat stress, enhancing lysine and threonine utilization under heat stress. 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. Thus, Dac6 couples nutrient sensing to thermal adaptation, illuminating a critical strategy for fungal survival.