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 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 protein translation by repressing the activity of the iron-dependent Rli1 ribosome recycling factor, inhibiting mitochondrial translation, and affecting the translation of genes involved in heme biosynthesis. We also discovered a mechanism, whereby iron deficiency represses translation of MRS3 mRNA, encoding mitochondrial iron transporter, through increased expression of antisense long non-coding RNA. Together, our results reveal complex gene expression and protein synthesis remodeling in response to low iron showing how this important metal affects protein translation at multiple levels.