Post-Transcriptional Regulation of the Sef1 Transcription Factor Controls the Virulence of <em>Candida albicans</em> in Its Mammalian Host

<div><p>The yeast <em>Candida albicans</em> transitions between distinct lifestyles as a normal component of the human gastrointestinal microbiome and the most common agent of disseminated fungal disease. We previously identified Sef1 as a novel Cys₆Zn₂ DNA binding protein that plays an essential role in <em>C. albicans</em> virulence by activating the transcription of iron uptake genes in iron-poor environments such as the host bloodstream and internal organs. Conversely, in the iron-replete gastrointestinal tract, persistence as a commensal requires the transcriptional repressor Sfu1, which represses <em>SEF1</em> and genes for iron uptake. Here, we describe an unexpected, transcription-independent role for Sfu1 in the direct inhibition of Sef1 function through protein complex formation and localization in the cytoplasm, where Sef1 is destabilized. Under iron-limiting conditions, Sef1 forms an alternative complex with the putative kinase, Ssn3, resulting in its phosphorylation, nuclear localization, and transcriptional activity. Analysis of <em>sfu1</em> and <em>ssn3</em> mutants in a mammalian model of disseminated candidiasis indicates that these post-transcriptional regulatory mechanisms serve as a means for precise titration of <em>C. albicans</em> virulence.</p>