Mln1 Coordinates Nutrient Sensing and Metabolic Adaptation for Host-Associated Survival in Human Fungal Pathogen Cryptococcus neoformans

Fungal pathogens must detect and respond to host-derived cues to survive during infection. To identify transcriptional regulators critical for host adaptation in the fungal meningitis pathogen Cryptococcus neoformans, we systematically screened for transcription factors (TFs) that are both induced under host-associated conditions and required for infectivity. Among 12 TFs responsive to elevated temperature or nutrient starvation, we identified MLN1, encoding a previously uncharacterized basic bHLH TF, as a central regulator of adaptation to carbon-limited environments. MLN1 expression was strongly induced under carbon and nitrogen starvation, and the Mln1 protein translocated to the nucleus during prolonged carbon depletion. Functional analyses revealed that deletion of MLN1 impaired the utilization of disaccharides and polyols, resulting in downregulation of genes involved in sugar transporters and amino acid transporters. These transcriptional defects were associated with reduced melanin production and impaired Titan cell formation. Transcriptome analysis showed that Mln1 orchestrates repression of nutrient transporters under nutrient-replete conditions and activates stress-responsive genes during carbon starvation. Although overall virulence was not significantly altered, mln1Δ mutants exhibited reduced fungal burden in the brain, underscoring the role of Mln1 in central nervous system survival. Together, our findings define a host-responsive transcriptional network and identify Mln1 as a key regulator that integrates nutrient sensing, metabolic adaptation, and virulence, thereby advancing our understanding of nutrient-driven transcriptional control in fungal pathogenesis.​