Abstract
Iron is an essential element for all eukaryotes, since it acts as a cofactor for many enzymes involved in basic cellular functions, including translation. While the mammalian iron-regulatory protein/iron-responsive element (IRP/IRE) system arose as one of the first examples of translational regulation in higher eukaryotes, little is known about the contribution of iron itself to the different stages of eukaryotic translation. In the yeast Saccharomyces cerevisiae, iron deficiency provokes a global impairment of translation at the initiation step, which is mediated by the Gcn2-eIF2α pathway, while the post-transcriptional regulator Cth2 specifically represses the translation of a subgroup of iron-related transcripts. In addition, several steps of the translation process depend on iron-containing enzymes, including particular modifications of translation elongation factors and transfer RNAs (tRNAs), and translation termination by the ATP-binding cassette family member Rli1 (ABCE1 in humans) and the prolyl hydroxylase Tpa1. The influence of these modifications and their correlation with codon bias in the dynamic control of protein biosynthesis, mainly in response to stress, is emerging as an interesting focus of research. Taking S. cerevisiae as a model, we hereby discuss the relevance of iron in the control of global and specific translation steps.
Highlights
Iron is an indispensable micronutrient for all eukaryotes and most prokaryotes due to its participation as a redox cofactor in fundamental cellular processes, including DNA replication and repair, cellular respiration, photosynthesis, oxygen transport, lipid metabolism, and, importantly, translation, which is the focus of the present review
We focus on the different iron-containing proteins that participate, either directly or indirectly, in the translation process and its regulation, with special emphasis on modifications of factors affecting translational elongation, post-transcriptional transfer RNA modifications (Elp3 and Dph3/Kti11 in the Elongator complex, wybutosine transfer RNAs (tRNAs) modification by Tyw1), and translational termination (Tpa1)
These data were supported by the analysis of previous yeast ribosome profiling data, as well as in human cells depleted of deoxyhypusine hydroxylase (DOHH), an enzyme involved in hypusination [92]
Summary
Iron is an indispensable micronutrient for all eukaryotes and most prokaryotes due to its participation as a redox cofactor in fundamental cellular processes, including DNA replication and repair, cellular respiration, photosynthesis, oxygen transport, lipid metabolism, and, importantly, translation, which is the focus of the present review. It has been known for years that mitochondria are indispensable for eukaryotic life This essentiality was first assigned to the multiple iron-dependent metabolic processes that take place in this organelle, including respiration. When this question was addressed more profoundly in the eukaryotic model Saccharomyces cerevisiae, which can grow in the absence of mitochondrial DNA, it was discovered that the minimal essential function of mitochondria relied on the biogenesis of cellular iron-sulfur (Fe/S) proteins (reviewed in [3]). ISC-containing proteins in numerous steps of translation, underscoring the importance of this element for this process and raising the question of how iron deficiency affects translation. Protein homologs in humans or other organisms, as well as related human diseases caused by their deficiencies, will be discussed when they are deemed relevant
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