Eukaryotic protein synthesis is initiated by binding of eIF4E to the 7-methylguanosine 5′ cap of mRNAs. Under hypoxic conditions, eIF4E is inhibited but protein synthesis continues to occur. Lee and colleagues sought to investigate whether an alternative pathway for translation initiation would account for the translation capacity of hypoxic cells. Previous work showed that hypoxia can activate EGFR mRNA translation through HIF-2α, a transcription factor that participates in the maintenance of oxygen homeostasis. The authors now find that HIF-2α associates with polysomes and with the 3′ UTR of EGFR mRNA in hypoxic cells, indicating that under these conditions HIF-2α's role goes beyond transcription. HIF-2α knockdown affected association of EGFR mRNA with polysomes and also decreased the global rates of hypoxic translation. RBM4, an RNA-binding protein involved in the control of translation, was found to interact with HIF-2α during hypoxia and is required for its recruitment to the EGFR 3′ UTR. RBM4 depletion affected hypoxic translation similarly to HIF-2α knockdown. Using PAR-CLIP, the authors identify a CGG motif that is important for the secondary structure of the EGFR 3′ UTR and essential for hypoxia-inducible translation. Further analysis of the PAR-CLIP data reveals similar CGG sites in most target reads, and the authors suggest that RBM4 recognizes RNA hypoxia-response elements (rHREs) in the 3′ UTR of mRNAs to recruit HIF-2α and initiate hypoxic translation. As the 3′ hHRE is able to induce hypoxia-dependent translation of transcripts with different 5′ UTRs that are otherwise not hypoxia inducible, the authors examined involvement of the 5′ cap. They found that HIF-2α–RBM4 assembles with eIF4E2, a cap-binding protein and eIF4E homolog, and that the complex binds to m7-GTP beads in an eIF4E2-dependent manner. In addition, eIF4E2 knockdown affected translation of multiple protein targets identified by PAR-CLIP. Finally, the authors find that cap-dependent translation machinery switches between eIF4E and eIF4E2 as a function of oxygen availability: eIF4E polysome association was observed under normal oxygen levels, whereas eIF4E2 was incorporated under hypoxia. The findings suggest an essential role for the HIF-2α–RBM4–eIF4E2 complex in oxygen homeostasis. (Nature doi:10.1038/nature11055, published online 6 March 2012)