Systematic analysis reveals an Mln1-dependent trade-off between metabolic flexibility and thermotolerance in Cryptococcus neoformans
- 1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Department of Integrative Biotechnolo
Abstract
During infection, fungal pathogens must adapt to multiple environmental challenges, including changes in temperature, nutrient availability, and immune stress. Although transcriptional regulators are central to these adaptations, how individual regulators contribute to distinct environmental responses and how these responses are functionally interconnected remain poorly understood. Here, we investigated the functions of infection-associated transcription factors under distinct host-relevant conditions in Cryptococcus neoformans. Integrating in vivo expression profiling with infectivity data from signature-tagged mutagenesis, we prioritized 24 transcription factors, 12 of which were induced under host-mimicking conditions. Initial functional analyses revealed distinct roles for these transcription factors in adaptation to temperature, carbon, and nitrogen availability. Further characterization of Mln1, a fungal basic helix-loop-helix transcription factor, uncovered an unexpected connection between carbon source adaptation and thermotolerance. Mig1-dependent repression limited MLN1 expression in the presence of glucose, whereas Mln1 accumulated in the nucleus in the presence of trehalose or ethanol, but not glucose. Loss of MLN1 impaired carbon-starvation gene expression and growth on non-preferred carbon sources, particularly trehalose. Conversely, mln1{Delta} cells accumulated more intracellular trehalose and exhibited enhanced thermotolerance, yet showed reduced melanization, titan cell formation, virulence in Drosophila, and brain fungal burden in mice. Together, these results suggest that Mln1 contributes to metabolic flexibility and fungal virulence while differentially influencing thermotolerance. More broadly, these findings highlight a potential physiological trade-off between nutrient utilization and stress resistance, suggesting that these adaptive processes may be interconnected in fungal pathogens.
Related
- Mapping virulence-associated protein interaction networks reveals regulators of thermotolerance in Cryptococcus neoformans
- Identification of Cryptococcus neoformans capsule-associated protein antigens that mediate B cell-dependent vaccine protection in mice and elicit antibody responses in humans with cryptococcosis
- Host Metabolic Reprogramming Defines Macrophage Antifungal Activity Against Cryptococcus neoformans
- Absence of a spindle position checkpoint in the fungal pathogen Cryptococcus neoformans
- Therapeutic vulnerabilities of the drug-resistant fungal meningitis pathogen Cryptococcus neoformans
BibTeX
@misc{yu2026systematic,
title = {{Systematic analysis reveals an Mln1-dependent trade-off between metabolic flexibility and thermotolerance in Cryptococcus neoformans}},
author = {S.-R. Yu and M. Lee and S.-Y. Yang and H. Cha and D. Won and D. Kim and J.-T. Choi and S. Yu and R. Seo and K.-A. Lee and J.-S. Lee and W.-J. Lee and D.-W. Lee and Y.-S. Bahn},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763006},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763006v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Systematic analysis reveals an Mln1-dependent trade-off between metabolic flexibility and thermotolerance in Cryptococcus neoformans
AU - S.-R. Yu
AU - M. Lee
AU - S.-Y. Yang
AU - H. Cha
AU - D. Won
AU - D. Kim
AU - J.-T. Choi
AU - S. Yu
AU - R. Seo
AU - K.-A. Lee
AU - J.-S. Lee
AU - W.-J. Lee
AU - D.-W. Lee
AU - Y.-S. Bahn
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763006
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763006v1
AB - During infection, fungal pathogens must adapt to multiple environmental challenges, including changes in temperature, nutrient availability, and immune stress. Although transcriptional regulators are central to these adaptations, how individual regulators contribute to distinct environmental responses and how these responses are functionally interconnected remain poorly understood. Here, we investigated the functions of infection-associated transcription factors under distinct host-relevant conditions in Cryptococcus neoformans. Integrating in vivo expression profiling with infectivity data from signature-tagged mutagenesis, we prioritized 24 transcription factors, 12 of which were induced under host-mimicking conditions. Initial functional analyses revealed distinct roles for these transcription factors in adaptation to temperature, carbon, and nitrogen availability. Further characterization of Mln1, a fungal basic helix-loop-helix transcription factor, uncovered an unexpected connection between carbon source adaptation and thermotolerance. Mig1-dependent repression limited MLN1 expression in the presence of glucose, whereas Mln1 accumulated in the nucleus in the presence of trehalose or ethanol, but not glucose. Loss of MLN1 impaired carbon-starvation gene expression and growth on non-preferred carbon sources, particularly trehalose. Conversely, mln1{Delta} cells accumulated more intracellular trehalose and exhibited enhanced thermotolerance, yet showed reduced melanization, titan cell formation, virulence in Drosophila, and brain fungal burden in mice. Together, these results suggest that Mln1 contributes to metabolic flexibility and fungal virulence while differentially influencing thermotolerance. More broadly, these findings highlight a potential physiological trade-off between nutrient utilization and stress resistance, suggesting that these adaptive processes may be interconnected in fungal pathogens.
ER -