Iron toxicity in yeast: transcriptional regulation of the vacuolar iron importer Ccc1

All eukaryotes require the transition metal, iron, a redox active element that is an essential cofactor in many metabolic pathways, as well as an oxygen carrier. Iron can also react to generate oxygen radicals such as hydroxyl radicals and superoxide anions, which are highly toxic to cells. Therefore, organisms have developed intricate mechanisms to acquire iron as well as to protect themselves from the toxic effects of excess iron. In fungi and plants, iron is stored in the vacuole as a protective mechanism against iron toxicity. Iron storage in the vacuole is mediated predominantly by the vacuolar metal importer Ccc1 in yeast and the homologous transporter VIT1 in plants. Transcription of yeast CCC1 expression is tightly controlled primarily by the transcription factor Yap5, which sits on the CCC1 promoter and activates transcription through the binding of Fe-S clusters. A second mechanism that regulates CCC1 transcription is through the Snf1 signaling pathway involved in low-glucose sensing. Snf1 activates stress transcription factors Msn2 and Msn4 to mediate CCC1 transcription. Transcriptional regulation by Yap5 and Snf1 are completely independent and provide for a graded response in Ccc1 expression. The identification of multiple independent transcriptional pathways that regulate the levels of Ccc1 under high iron conditions accentuates the importance of protecting cells from the toxic effects of high iron.