Iron in Translation: From the Beginning to the End (original) (raw)
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Scientific Reports, 2020
Iron is an essential element for all eukaryotic organisms because it participates as a redox active cofactor in a wide range of biological processes, including protein synthesis. Translation is probably the most energy consuming process in cells. Therefore, one of the initial responses of eukaryotic cells to stress or nutrient limitation is the arrest of mRNA translation. In first instance, the budding yeast Saccharomyces cerevisiae responds to iron deficiency by activating iron acquisition and remodeling cellular metabolism in order to prioritize essential over non-essential iron-dependent processes. We have determined that, despite a global decrease in transcription, mRNA translation is actively maintained during a short-term exposure to iron scarcity. However, a more severe iron deficiency condition induces a global repression of translation. Our results indicate that the Gcn2-eIF2α pathway limits general translation at its initiation step during iron deficiency. This bulk transl...
Genome-wide ribosome profiling uncovers the role of iron in the control of protein translation
Iron is an essential trace element that serves as a cofactor for enzymes involved in multiple metabolic pathways, including ribosome biogenesis, protein translation, DNA synthesis and repair, lipid metabolism, and mitochondrial oxidative phosphorylation. In eukaryotes, iron deficiency leads to global inhibition of protein synthesis and coordinated changes in gene expression to limit iron utilization. Although several steps of protein translation depend on iron-containing enzymes, the contribution of iron to the translation process is not understood at the molecular level. Here, we report a genome-wide analysis of protein translation in response to iron deficiency in yeast using ribosome profiling. We show that iron depletion affects global protein synthesis as well as leads to translational repression of several groups of genes involved in iron-related processes. We further demonstrate that the RNA-binding proteins Cth1 and Cth2 play a central role in controlling the changes in prot...
Dissecting mRNA decay and translation inhibition during iron deficiency
Current Genetics, 2018
Iron participates as a vital cofactor in multiple metabolic pathways. Despite its abundance, iron bioavailability is highly restricted in aerobic and alkaline environments. Therefore, living organisms have evolved multiple adaptive mechanisms to respond to iron scarcity. These strategies include a global remodeling of iron metabolism directed to optimize iron utilization. In the baker's yeast Saccharomyces cerevisiae, this metabolic reorganization is accomplished to a large extent by an mRNA-binding protein called Cth2. Yeast Cth2 belongs to a conserved family of tandem zinc finger containing proteins that specifically bind to transcripts containing AU-rich elements and promote their turnover. A recent study has revealed that Cth2 also inhibits the translation of its target mRNAs. Interestingly, the mammalian Cth2 ortholog known as tristetraprolin (aka TTP/TIS11/ZFP36), which is also implicated in controlling iron metabolism, promotes the decay and prevents the translation of its regulated transcripts. These observations open the possibility to study the relative contribution of altering mRNA stability and translation to the physiological adaptation to iron deficiency, the function played by the different domains within the mRNA-binding protein, and the potential factors implicated in coordinating both post-transcriptional events.
Yeast Cth2 protein represses the translation of ARE-containing mRNAs in response to iron deficiency
PLoS genetics, 2018
In response to iron deficiency, the budding yeast Saccharomyces cerevisiae undergoes a metabolic remodeling in order to optimize iron utilization. The tandem zinc finger (TZF)-containing protein Cth2 plays a critical role in this adaptation by binding and promoting the degradation of multiple mRNAs that contain AU-rich elements (AREs). Here, we demonstrate that Cth2 also functions as a translational repressor of its target mRNAs. By complementary approaches, we demonstrate that Cth2 protein inhibits the translation of SDH4, which encodes a subunit of succinate dehydrogenase, and CTH2 mRNAs in response to iron depletion. Both the AREs within SDH4 and CTH2 transcripts, and the Cth2 TZF are essential for translational repression. We show that the role played by Cth2 as a negative translational regulator extends to other mRNA targets such as WTM1, CCP1 and HEM15. A structure-function analysis of Cth2 protein suggests that the Cth2 amino-terminal domain (NTD) is important for both mRNA t...
Gene expression and protein synthesis remodeling in response to iron deficiency in yeast
Iron is an essential trace element that serves as a cofactor for enzymes involved in multiple metabolic pathways, including ribosome biogenesis, protein translation, DNA synthesis and repair, lipid metabolism, and mitochondrial oxidative phosphorylation. In eukaryotes, iron deficiency leads to coordinated changes in gene expression and protein translation that activate iron uptake and allow metabolic adaptations of iron-dependent processes. While transcriptional responses to iron deprivation have been extensively characterized, little is known about the role of iron in regulating protein synthesis. In this study, we performed a genome-wide analysis of protein translation in yeast to identify transcripts translationally regulated under iron deficiency. We show that, upon iron depletion, a large set of genes necessary for mitochondrial protein synthesis is specifically down-regulated at the translational level. We demonstrate that this regulation is mediated through the activity of Ct...
Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation
The International Journal of Biochemistry & Cell Biology, 1999
Iron plays a central role in the metabolism of all cells. This is evident by its major contribution to many diverse functions, such as DNA replication, bacterial pathogenicity, photosynthesis, oxidative stress control and cell proliferation. In mammalian systems, control of intracellular iron homeostasis is largely due to posttranscriptional regulation of binding by iron-regulatory RNA-binding proteins (IRPs) to iron-responsive elements (IREs) within ferritin and transferrin receptor (TfR) mRNAs. The TfR transports iron into cells and the iron is subsequently stored within ferritin. IRP binding is under tight control so that it responds to changes in intracellular iron requirements in a coordinate manner by dierentially regulating ferritin mRNA translational eciency and TfR mRNA stability. Several dierent stimuli, as well as intracellular iron levels and oxidative stress, are capable of regulating these RNA±protein interactions. In this mini-review, we shall concentrate on the mechanisms underlying modulation of the interaction of IRPs and the ferritin IRE and its role in regulating ferritin gene expression.
Post-Transcriptional Regulation of Iron Homeostasis in Saccharomyces cerevisiae
International Journal of Molecular Sciences, 2013
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 Cx 8 Cx 5 Cx 3 H 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.
Redox control of iron regulatory proteins
Redox Report, 2002
Iron is an essential cellular constituent but, on the other hand, possesses an enormous toxic capacity when present in excess. This is largely due to Fenton/Haber-Weiss chemistry, e.g. the aerobic iron-catalyzed generation of aggressive radicals, which readily attack and damage cell membranes, proteins and nucleic acids. 1 Thus, the regulation of iron homeostasis poses a challenge not only to satisfy the metabolic needs of cells and organisms for iron, but also to minimize the risk of iron-induced injury.
The Journal of biological chemistry, 1988
Ferritin, a cytoplasmic protein critical in iron metabolism, displays iron-dependent regulation of its biosynthetic rate with no corresponding changes in mRNA levels. An iron-responsive element (IRE) has been identified in the 5'-untranslated region (UTR) of the human ferritin heavy chain mRNA which, when placed in the 5'-UTR of heterologous reporter genes, confers iron-dependent translational regulation to the hybrid mRNAs. However, whereas the biosynthetic rate of ferritin in response to changes in iron status exhibits a 30-80-fold range, the apparent ranges observed for reporter gene constructs utilizing chloramphenicol acetyltransferase assays or human growth hormone radioimmunoassays have been much less. A deletion and reconstitution study was undertaken to address the possibility that regions of the ferritin gene and mRNA other than the IRE may be necessary for the production of the full range of iron regulation. Data are presented that demonstrate that the IRE alone i...