Iron in Translation: From the Beginning to the End

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.

Keywords: Saccharomyces cerevisiae; iron deficiency; tRNA modification; translation; yeast.

Figure 1

Mechanisms of regulation of protein synthesis in response to iron deficiency in the budding yeast S. cerevisiae at different levels. Upon iron depletion, TORC1 complex is inactivated, leading to (1) repression of RP and RiBi genes transcription by Tod6, Dot6, Stb3, and Rpd3L complex, and export of their transcriptional activator Sfp1 to the cytosol; (2) inhibition of RNA Pol III by association to its dephosphorylated Maf1 repressor; and (3) inhibition of RNA Pol I activity due to the decrease in the levels of its Rnr3 activator [12]. Moreover, (4) phosphorylation of eIF2α by Gcn2 inhibits global protein synthesis at the initiation stage in a Gcn1-Gcn20-dependent manner and promotes GCN4 mRNA translation [36].

Figure 2

Iron-dependent proteins involved in the modification of the elongation factors eEF2 and eIF5A in the budding yeast S. cerevisiae. (A) Enzymatic steps in the diphthamide modification of eEF2. The ISCs in Dph1 and Dph2 are represented by red circles (iron nuclei) and blue circles (sulfur nuclei). Red circles in Dph3 and Dph4 represent mononuclear iron cofactors. Me means CH₃. (B) Enzymatic steps in the hypusine modification of eIF5A. Red circles in Lia1 represent a binuclear iron cofactor.

Figure 3

Iron-dependent proteins involved in the different steps of translation and in tRNA modifications in the budding yeast S. cerevisiae. In Rli1, Elp3, and Tyw1, ISCs are represented by red circles (iron nuclei) and blue circles (sulfur nuclei). Red circles in Dph3 and Tpa1 represent mononuclear iron cofactors.