Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2\u03b1 pathway

Antonia María Romero,Paula Alepuz,Sergi Puig,María Teresa Martínez-Pastor,Lucía Ramos-Alonso

doi:10.1038/s41598-019-57132-0

Abstract

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 translational inhibition depends on the uncharged tRNA sensing Gcn1-Gcn20 complex. The involvement of the Gcn2-eIF2α pathway in the response to iron deficiency highlights its central role in the eukaryotic response to stress or nutritional deprivation, which is conserved from yeast to mammals.

Highlights

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
To investigate whether iron deprivation alters the efficiency of bulk mRNA translation, we determined the polysome profile of wild-type W303 yeast cells cultivated in iron-sufficient (+Fe) or iron-deficient conditions (−Fe), achieved by the addition of 100 μM of the Fe2+-specific chelator bathophenanthroline disulfonic acid (BPS)
Opposite to glucose starvation and other nutritional stresses characterized by a rapid arrest of mRNA translation, iron deficiency is a nutritional disorder which effects are not immediate

Summary

Introduction

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. Upon amino acid deprivation or exposure to different stress conditions, Gcn[2] protein kinase phosphorylates the alpha subunit of eIF2 (eIF2α), converting eIF2 into an eIF2B inhibitor, which causes a decrease in the levels of ternary complex and a block in global 5′ cap-dependent translation initiation.

Results

Conclusion