Mrv6 modulates membrane ergosterol homeostasis to control hyphal signaling and virulence in Candida albicans

Candida albicans orchestrates complex cellular responses to sense host environmental cues and execute virulence programs. In this study, we characterize Mrv6, a MARVEL domain-containing membrane protein that is prominently induced by genotoxic stress. Intriguingly, the deletion of MRV6 unexpectedly conferred increased resistance to the alkylating agent MMS while profoundly attenuating fungal virulence in a Galleria mellonella infection model. Mechanistically, we demonstrate that Mrv6 acts as a critical governor of ergosterol homeostasis rather than a canonical DNA repair factor. Loss of MRV6 triggered global transcriptional reprogramming of the ergosterol biosynthetic pathway, leading to aberrant cellular ergosterol accumulation. This ergosterol imbalance results in a significantly "tightened" plasma membrane with reduced permeability. While this rigid membrane structure shielded the fungus from exogenous toxins, it fatally restricted the intracellular entry of morphogenetic signals under hypoxic conditions. As a result of this sensing blockade, the major filamentous repressor NRG1 remained aberrantly highly expressed, trapping the pathogen in an avirulent yeast state. Crucially, targeted genetic suppression of either ERG1 or NRG1 effectively bypassed this signaling blockade, restoring morphogenetic switching and pathogenicity in the mrv6Δ mutant. Collectively, our findings reveal an unprecedented pathogenic strategy where C. albicans rewires ergosterol homeostasis via a stress-responsive protein to modulate membrane permeability, highlighting Mrv6 as a novel mechanosensory node connecting the DNA damage response to environmental sensing and full virulence.