Ergosterol remodeling by the MARVEL protein Mrv6 links genotoxic stress adaptation to virulence in Candida albicans

How fungal pathogens coordinate genotoxic stress responses with membrane homeostasis to sustain cellular signaling remains poorly understood. In this study, we characterize Mrv6, a MARVEL domain-containing membrane protein that is prominently induced by genotoxic stress. Intriguingly, rather than functioning as a canonical DNA repair factor, Mrv6 acts as a critical biophysical adjuster governing membrane lipid homeostasis. Deletion of MRV6 triggers a global transcriptional activation of the ergosterol biosynthetic pathway, resulting in aberrant cellular ergosterol accumulation. We demonstrate that this lipid imbalance fundamentally alters plasma membrane homeostasis, resulting in a less permeable architecture. Paradoxically, while this structural alteration inadvertently shields the fungus from exogenous genotoxins, conferring unexpected resistance to methyl methanesulfonate, it simultaneously hinders the intracellular transduction of environmental morphogenetic signals under hypoxic conditions. Consequently, the major hyphal repressor NRG1 remains aberrantly expressed, leading to an attenuated signaling response that significantly impairs virulence. Crucially, targeted genetic suppression of either the lipid biosynthetic node (ERG1) or the downstream signaling node (NRG1) effectively mitigates this biophysical constraint, rescuing both morphogenetic switching and pathogenicity. Collectively, our findings define a novel biochemical paradigm wherein Candida albicans utilizes a stress-responsive membrane protein to fine-tune ergosterol remodeling and membrane permeability, structurally coupling stress adaptation to signal transduction.