Transcriptional regulation of ergosterol biosynthesis genes in response to iron deficiency

Iron participates as an essential cofactor in the biosynthesis of critical cellular components, including DNA, proteins and lipids. The ergosterol biosynthetic pathway, which is an important target of antifungal treatments, depends on iron in four enzymatic steps. Our results in the model yeast Saccharomyces cerevisiae show that the expression of ergosterol biosynthesis (ERG) genes is tightly modulated by iron availability probably through the iron-dependent variation of sterol and heme levels. Whereas the transcription factors Upc2 and Ecm22 are responsible for the activation of ERG genes upon iron deficiency, the heme-dependent factor Hap1 triggers their Tup1-mediated transcriptional repression. The combined regulation by both activating and repressing regulatory factors allows for the fine-tuning of ERG transcript levels along the progress of iron deficiency, avoiding the accumulation of toxic sterol intermediates and enabling efficient adaptation to rapidly changing conditions. The lack of these regulatory factors leads to changes in the yeast sterol profile upon iron-deficient conditions. Both environmental iron availability and specific regulatory factors should be considered in ergosterol antifungal treatments.
This research was supported by grant PID2020-116940RB-I00 funded by MCIN/AEI/10.13039/501100011033 to Sergi Puig, grants PID2020-120066RB-I00 funded by MCIN/AEI/10.13039/501100011033 and AICO/2020/086 by ‘Generalitat Valenciana’ to Paula Alepuz, and grant RED2018-102467-T funded by MCIN/AEI/10.13039/501100011033 to Sergi Puig and Paula Alepuz. Tania Jordá was a recipient of a predoctoral fellowship ACIF/2019/214 funded by ‘Generalitat Valenciana’, and Marina Barba-Aliaga was a recipient of a predoctoral fellowship (FPU2017/03542) funded by MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future. The authors also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).