A deacetylase governs thermotolerance and pathogenicity by regulating host amino-acid utilization in Cryptococcus neoformans

Thermotolerance is critical for fungal survival in vivo, yet how metabolic remodeling enables pathogenic fungi such as Cryptococcus neoformans to withstand heat stress remains unclear. Here, we identify the protein deacetylase Dac6 as a thermotolerance regulator in C. neoformans functioning independently of the yeast deacetylase Rpd3 and mirroring the heat-resistant phenotype of clinical isolates. Integrated multi-omics analyses reveal that Dac6 remodels histone acetylation and gene expression to reprogram amino acid metabolism under heat stress, thereby enhancing lysine and threonine utilization. Lysine and threonine are also among the most markedly altered metabolites in the host during cryptococcal infection, and Dac6 deletion impairs fungal utilization of these amino acids 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 utilization to thermal adaptation, revealing a chromatin-guided metabolic strategy that supports fungal survival in the host.