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

Abstract

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.

Fungal–Metal Interactions: A Review of Toxicity and Homeostasis

“…Interference of vacuolar transport encoding gene CCC1 [91,92] Inability to acquire iron [60,93] Manganese Down-regulation of HTB2, HTA1, HTA1, HTBI, HHF [94,95] potentially associated to reduced functioning of manganese peroxidase [96][97][98] Silver Interference in ergosterol biosynthesis [80,99,100] --…”

“…Results indicated that, during corneal fungal infection, these fungi acquired iron through siderophores and that the iron-binding agent blocked the ability of the pathogen to acquire siderophore-bound iron, highlighting the inability of the fungi to proliferate without access to iron [93]. In S. cerevisiae, iron toxicity is related to the ability of the cell to transport cytosolic iron to the vacuole via Ccc1 [91,248]. Lin et al showed that ccc1∆ mutants could not transfer cytosolic iron to the vacuole under anaerobic conditions, even with the overexpression of iron mitochondrial transporter Mrs3, effectively inducing toxicity [248].…”

Iron Regulatory Mechanisms in Saccharomyces cerevisiae

“…The yeast iron detoxification response is mostly triggered by the transcriptional activator protein of the Yap family, Yap5 [reviewed in Li and Ward (2018) ; Rodrigues-Pousada et al (2019) ]. Yap5 associates to Yap response elements (YREs) within the promoter of its target genes independently of iron levels, but only activates transcription when it associates to two [2Fe–2S] clusters through conserved cysteine-rich domains in a mitochondrial ISC-dependent but Grx3/4-independent manner ( Li et al, 2008 , 2012 ; Rietzschel et al, 2015 ).…”

Structure and function of the vacuolar Ccc1/VIT1 family of iron transporters and its regulation in fungi

“…Consistent with its crucial function in cytosolic iron detoxification, the expression of CCC1 is finely regulated by iron. In response to iron excess, S. cerevisiae Yap5, a member of the yeast activator protein (Yap) subfamily of transcriptional factors (reviewed in [53] ), activates the expression of CCC1 ( [54] ; reviewed in [55] ) ( Fig. 4 ).…”