An oxygen-regulated switch in the protein synthesis machinery.
Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m(7)-GpppG) 5' cap of messenger RNAs. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms. Although the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells. This raises a fundamental question in 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. We show that hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2α (HIF-2α), the RNA-binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array of mRNAs, including that encoding the epidermal growth factor receptor. Once assembled at the rHRE, the HIF-2α-RBM4-eIF4E2 complex captures the 5' cap and targets mRNAs to polysomes for active translation, thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program by which oxygen tension switches the basic translation initiation machinery.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
James
J
Uniacke
Chet E
CE
Holterman
Gabriel
G
Lachance
Aleksandra
A
Franovic
Mathieu D
MD
Jacob
Marc R
MR
Fabian
Josianne
J
Payette
Martin
M
Holcik
Arnim
A
Pause
Stephen
S
Lee
D020413:3' Untranslated Regions / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D039381:RNA Cap-Binding Proteins / Q000378:metabolism; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D020413:3' Untranslated Regions; D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D039561:Eukaryotic Initiation Factor-4E; D051793:Hypoxia-Inducible Factor 1; D010100:Oxygen; D039381:RNA Cap-Binding Proteins; D012315:RNA Caps; D016601:RNA-Binding Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C112609:EIF4E2 protein, human; C473692:RBM4 protein, human