Post-Transcriptional Regulation of the Sef1 Transcription Factor Controls the Virulence of <em>Candida albicans</em> 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.白色念珠菌（Candida albicans）可在多种截然不同的生活方式间切换：它既是人类胃肠道微生物组的正常组分，亦是播散性真菌病的最常见致病菌。此前我们将Sef1鉴定为一种新型Cys6Zn2型DNA结合蛋白，它可在宿主血流及内脏等缺铁环境中，通过激活铁摄取基因的转录，对白色念珠菌的毒力发挥至关重要的作用。与之相反，在铁含量充足的胃肠道中，白色念珠菌要作为共生菌定植，则需要转录阻遏蛋白Sfu1——它可抑制SEF1以及铁摄取相关基因的表达。本研究揭示了Sfu1此前未被报道的、不依赖转录的全新功能：它可通过与Sef1形成蛋白质复合物并将其锚定在细胞质内，直接抑制Sef1的功能，进而导致Sef1稳定性下降。在缺铁条件下，Sef1会与推定激酶Ssn3形成另一种复合物，进而发生磷酸化、获得核定位能力并激活转录活性。我们通过播散性念珠菌病的哺乳动物模型对sfu1与ssn3突变体进行分析后发现，上述转录后调控机制可精准调控白色念珠菌的毒力水平。