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.
Authors
- Ziwei Dai (ORCID: https://orcid.org/0000-0002-0858-638X)
- Xindi Gao (ORCID: https://orcid.org/0009-0008-5850-1250)
- Keting Zhu (ORCID: https://orcid.org/0000-0001-8402-8913)
- Tingying Xu (ORCID: https://orcid.org/0000-0002-8261-3796)
- Yue Ni (ORCID: https://orcid.org/0009-0002-3461-5727)
- Chao Li (ORCID: https://orcid.org/0000-0003-4240-1382)
- Qianqian Zheng (ORCID: https://orcid.org/0000-0001-5906-148X)
- Lei Chen
- Wei Huang
- Chun Feng
- Chen Ding
- Yanjian Li
- Tianshu Sun
- Renjie Zhou
- Hailong Li
- Kun Yu
- Zhijing Song
- Xiaolu Yang
- Yue Qiao
- He Yan
- Yang Meng
- Di Liu
Institutions
- Army Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Southern University of Science and Technology (CN)
- Institute of Biophysics (CN)
- Xinqiao Hospital (CN)
- National Institutes for Food and Drug Control (CN)
- First Hospital of China Medical University (CN)
- China Medical University (CN)
- Northeastern University (CN)
Publication Details
- Journal
- Microbiological Research
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1016/j.micres.2026.128807
- Primary Topic
- Fungal Infections and Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Chongqing
- Army Medical University
- National Key Research and Development Program of China