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

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. Synopsis In Drosophila , the cap‐binding protein eIF4EHP promotes Lactate dehydrogenase (LDH) production under hypoxia by controlling Ldh mRNA translation through a CA‐rich motif in the 3′UTR. eIF4EHP is required for adaptation to hypoxic conditions. While hypoxia induces a strong reduction in protein synthesis, the Ldh mRNA encoding lactate dehydrogenase is efficiently translated into hypoxic Drosophila cells. Ldh mRNA translation is controlled in cis by a CA‐rich 3′UTR element and in trans by the translation initiation factor eIF4EHP. In hypoxic cells, eIF4EHP binds to Ldh mRNA, associates with polysomes, and accumulates in cytoplasmic granules. Downregulation of eIF4EHP inhibits the development of Drosophila melanogaster under reduced oxygen levels and impairs recovery from hypoxia in adult flies. Graphical Abstract In Drosophila , the cap‐binding protein eIF4EHP promotes Lactate dehydrogenase (LDH) production under hypoxia by controlling Ldh mRNA translation through a CA‐rich motif in the 3′UTR. eIF4EHP is required for adaptation to hypoxic conditions.