Cellular adaptation to low oxygen availability by a switch in the protein synthesis machinery

Abstract

Protein synthesis is a classic molecular mechanism of cell biology that is taught in introductory biology classrooms. It involves the translation of messenger ribonucleic acid (mRNA) information into proteins, the building blocks of life. The initial step of protein synthesis consists of the eu¬karyotic translation initiation factor 4E (eIF4E) binding to the 5’cap of mRNAs. A variety of stress¬es repress translation to conserve energy because protein synthesis requires over half of a cell’s energy supply. An important stress for multicellular animals is low oxygen availability (hypoxia). This causes a repression of cap-directed translation by inhibiting eIF4E. This raises a fundamental question in cell biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition. Here, we describe an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. Hypoxia stimulates the formation of a complex that in¬cludes the oxygen-regulated hypoxia-inducible factor 2α (HIF-2α), the RNA binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. We also identified an RNA hypoxia response ele¬ment (rHRE) that recruits this complex to a wide array of mRNAs, including the epidermal growth factor receptor (EGFR), which plays a role in growth signaling and proliferation. Once assembled at the rHRE, HIF-2α/RBM4/eIF4E2 captures the 5’cap and targets mRNAs for active translation thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program whereby oxygen availability switches the basic translation initiation machinery.