HIF-2α binds RBM4 and eIF4E2 and regulates target mRNA translation in hypoxic conditions.
Major finding: HIF-2α binds RBM4 and eIF4E2 and regulates target mRNA translation in hypoxic conditions.
Mechanism: A HIF-2α–dependent switch from eIF4E to eIF4E2 promotes EGFR, PDGFRA, and IGF1R translation.
Impact: Cancer cells may co-opt eIF4E2-dependent translation to overproduce oncogenic proteins.
When cellular oxygen levels are depleted, translation is largely repressed by mTOR-dependent inhibition of eukaryotic translation initiation factor 4E (eIF4E). It is not completely understood how cells growing in hypoxic conditions, particularly oxygen-deprived tumor cells that are far removed from a blood supply, continue to synthesize proteins. Uniacke and colleagues provide evidence that hypoxia-inducible factor-2α (HIF-2α), a transcription factor that regulates oxygen homeostasis, is also a component of a hypoxia-inducible translation initiation complex that regulates selective protein synthesis. Under hypoxic conditions, epidermal growth factor receptor (EGFR) accumulated in glioblastoma cells in a HIF-2α–dependent manner, even when transcription was blocked. HIF-2α, but not the related protein HIF-1α, fractionated with ribosomes, indicating that it directly interacts with the translation machinery. Together with the translational control protein RNA-binding motif 4 (RBM4), HIF-2α bound to EGFR mRNA as well as many other transcripts with a similar RNA hypoxia response element (rHRE) sufficient to confer hypoxic translation. Among translation initiation proteins, HIF-2α and RBM4 specifically interacted with eIF4E2, a homolog of eIF4E. eIF4E2 was specifically required for hypoxic translation of multiple proteins, including EGFR, platelet-derived growth factor receptor A (PDGFRA), and insulin-like growth factor-1 receptor (IGF1R), whereas eIF4E only regulated translation of these proteins in normal oxygen concentrations. Interestingly, knockdown of HIF-2α blocked the inclusion of eIF4E2 into the translation initiation machinery in hypoxic cells, suggesting HIF-2α mediates the formation of a hypoxia-specific translation initiation complex that induces the translation of rHRE-containing transcripts in response to low oxygen levels. Together, these findings raise the intriguing possibility that tumor cells may preferentially utilize eIF4E2-mediated translation to bypass translational control mechanisms in hypoxic conditions and overproduce specific proteins that confer a proliferative advantage.