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

The yeast Candida albicans 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 C. albicans 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 SEF1 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 sfu1 and ssn3 mutants in a mammalian model of disseminated candidiasis indicates that these post-transcriptional regulatory mechanisms serve as a means for precise titration of C. albicans virulence. Candida albicans is a fungus that resides on the skin and in the gastrointestinal tract of humans and other mammals. However, this commensal organism is also capable of proliferating and causing disease in people who have received antibiotics, who are immunocompromised, or who have suffered injury to epithelial layers. We previously identified a novel transcription factor called Sef1 that promotes C. albicans virulence by activating the expression of iron uptake genes in iron-poor environments, such as the host bloodstream. However, in iron-replete environments such as the gastrointestinal niche, the SEF1 gene is repressed by a second transcription factor called Sfu1. Here, we report our discovery of a series of post-transcriptional regulatory events that determine the intracellular localization, stability, and activity of Sef1 protein. Mutants that disrupt these post-transcriptional events alter C. albicans virulence in a mammalian model of disseminated infection. The existence of multiple levels of regulation speaks to the importance of Sef1 in C. albicans virulence and suggests that close titration of Sef1 activity is important for adaptation to distinct microenvironments within the mammalian host.