Post-Transcriptional Regulation of Iron Homeostasis in Saccharomyces cerevisiae

Abstract

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in a wide variety of biological processes. Recent studies in Saccharomyces cerevisiae have shown that in response to iron deficiency, an RNA-binding protein denoted Cth2 coordinates a global metabolic rearrangement that aims to optimize iron utilization. The Cth2 protein contains two Cx8Cx5Cx3H tandem zinc fingers (TZFs) that specifically bind to adenosine/uridine-rich elements within the 3′ untranslated region of many mRNAs to promote their degradation. The Cth2 protein shuttles between the nucleus and the cytoplasm. Once inside the nucleus, Cth2 binds target mRNAs and stimulates alternative 3′ end processing. A Cth2/mRNA-containing complex is required for export to the cytoplasm, where the mRNA is degraded by the 5′ to 3′ degradation pathway. This post-transcriptional regulatory mechanism limits iron utilization in nonessential pathways and activates essential iron-dependent enzymes such as ribonucleotide reductase, which is required for DNA synthesis and repair. Recent findings indicate that the TZF-containing tristetraprolin protein also functions in modulating human iron homeostasis. Elevated iron concentrations can also be detrimental for cells. The Rnt1 RNase III exonuclease protects cells from excess iron by promoting the degradation of a subset of the Fe acquisition system when iron levels rise.

The J anus transcription factor H ap X controls fungal adaptation to both iron starvation and iron excess

“…Aft1 and Aft2 transcriptionally activate iron acquisition as well as Cth1 and Cth2. These two paralogous mRNA-binding proteins mediate post-transcriptional repression of iron consumption by promoting respective mRNA degradation, including the homolog of A. fumigatus cccA (Martinez-Pastor et al , 2013). These data demonstrate complete regulatory rewiring of vacuolar iron storage in this yeast compared to A. fumigatus, with different regulators being required for activation and repression.…”

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway

“…www.nature.com/scientificreports www.nature.com/scientificreports/ regulatory mechanisms that promote the entrance of the scarce extracellular iron, the mobilization of intracellular iron stores, and the remodeling of iron metabolism in order to prioritize essential iron-dependent processes versus dispensable ones 6,8,33 . Therefore, no dramatic arrest of protein synthesis has been described after exposure to iron deficiency, which has been supported by the robust homeostasis of amino acid levels 34,35 .…”

Molecular basis of the regulation of iron homeostasis in fission and filamentous yeasts

“…In bacteria and S. cerevisiae , iron‐sparing mechanisms operate mainly at the post‐transcriptional level. These mechanisms involve specialized small RNAs (bacteria) and RNA‐binding proteins ( S. cerevisiae ) that trigger selective elimination of specific transcripts with the help of RNA degradation systems . In the cases of S. pombe and filamentous fungi, a specialized subunit of the CCAAT‐binding factor is synthesized under low‐iron conditions .…”