eIF4EHP promotes Ldh mRNA translation in and fruit fly adaptation to hypoxia.

ABSTRACT

Hypoxia induces profound modifications in the gene expression program of eukaryotic cells due to lowered ATP supply resulting from the blockade of oxidative phosphorylation. One significant consequence of oxygen deprivation is the massive repression of protein synthesis, leaving a limited set of mRNAs to be translated. Drosophila melanogaster is strongly resistant to oxygen fluctuations; however, the mechanisms allowing specific mRNA to be translated into hypoxia are still unknown. Here, we show that Ldh mRNA encoding lactate dehydrogenase is highly translated into hypoxia by a mechanism involving a CA-rich motif present in its 3' untranslated region. Furthermore, we identified the cap-binding protein eIF4EHP as a main factor involved in 3'UTR-dependent translation under hypoxia. In accordance with this observation, we show that eIF4EHP is necessary for Drosophila development under low oxygen concentrations and contributes to Drosophila mobility after hypoxic challenge. Altogether, our data bring new insight into mechanisms contributing to LDH production and Drosophila adaptation to oxygen variations.