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

ABSTRACT: 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.

ORGANISM(S): Cryptococcus neoformans Saccharomyces cerevisiae

PROVIDER: GSE302506 | GEO | 2025/11/25

REPOSITORIES: GEO

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Project description:WD40 motif-containing Msi1-like (MSIL) proteins play pleiotropic cellular functions as a negative regulator of the Ras/cAMP-pathways and a component of chromatin assembly factor-I (CAF-I), and yet have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which can cause fatal meningoencephalitis in humans. Notably, Msl1 was not a functional ortholog for the yeast Msi1 but played pleiotropic roles in C. neoformans in both cAMP-dependent and -independent manners but mainly Ras-independently. Msl1 negatively controlled antioxidant melanin production and sexual differentiation, which can be repressed by inhibiting the cAMP-signaling pathways. In contrast, Msl1 controlled thermotolerance, diverse stress responses, and antifungal drugs resistance in Ras/cAMP-independent manners. Cac2, which is the second CAF-I component, appeared to play both redundant and distinct function with Msl1. Msl1 is required for full virulence of C. neoformans. Transcriptome and proteomic analysis identified a group of Msl1-regulated genes or -interacting proteins, respectively, which mostly include stress-related genes, including HSP12, HSP78, SSA1, SSA4, and STM1. Furthermore, we identified the third putative component of CAF-1, Rlf2, in C. neoformans. In conclusion, this study demonstrated the pleiotropic roles of Msl1 in human fungal pathogen C. neoformans, providing a novel antifungal therapeutic target. There is more than 95% genome homology between JEC21 and H99. Therefore, 6 slides of JEC21 (Cryptococcus neoformans var. neoformans serotype D) 70-mer oligos are used in this analysis. Total RNAs are extracted from 2 strains from H99 (H99 wild-type strain (Cryptococcus neoformans var. grubii serotype A), msl1M-NM-^T). 3 biological replicate experiments are performed for each strain. We use the mix of all total RNAs from this experiment as the control RNA. We use Cy3 as the test sample dye and Cy5 as the control dye.

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

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