An oxygen-regulated switch in the protein synthesis machinery
Open accessAbstract
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.
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HIF-2α is part of a hypoxia-regulated translation initiation complex; hypoxia induces formation of a HIF-2α complex with RBM4 and eIF4E2, which is recruited to mRNAs to promote active translation at polysomes.
“Hypoxia induces the formation of a HIF-2α complex with the RNA-binding protein RBM4 and cap-binding protein eIF4E2, which is then recruited to a wide variety of mRNAs to promote active translation at polysomes (Uniacke et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Uniacke et al., 2012
This HIF-2α translation function is independent of HIF-1β dimerization.
“This function is independent of HIF-1β dimerization.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Uniacke et al., 2012
HIF-2α is able to combine with RBM4 at hypoxia response elements within the 3'UTR of a selective sub-set of mRNAs to initiate translation under hypoxic conditions.
“More recently, it has been proposed that HIF-2α is able to combine with RBM4 at hypoxia response elements within the 3'UTR of a selective sub-set of mRNAs to initiate translation under hypoxic conditions (539).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [539]
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- Authors
- Uniacke, J., Holterman, C. E., Lachance, G., Franovic, A., Jacob, M. D., Fabian, M. R., Payette, J., Holcik, M., Pause, A., & Lee, S.
- Affiliations
- University of Ottawa (CA)
- McGill University (CA)
- Corresponding author
- Lee, Stephen
- ORCID
- Venue
- Nature
- Published
- 2012-05-06
- Volume
- 486
- Issue
- 7401
- Pages
- 126-129
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4974072
- OpenAlex
- W2013932632
- Cited by
- 319
- References
- 32
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 16 · 2023: 31 · 2022: 22 · 2021: 27 · 2020: 28 · 2019: 26 · 2018: 18 · 2017: 26 · 2016: 21 · 2015: 23 · 2014: 33 · 2013: 16 · 2012: 4
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Canadian Institutes of Health Research (89780_1, 74740_2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia, translation initiation, eIF4E, eIF4E2, HIF-2α, RBM4, hypoxia response element, mRNA cap binding, selective translation, mTOR, epidermal growth factor receptor, polysomes, oxygen regulation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Cell Line, Humans, Oxygen, Peptide Chain Initiation, Translational, Polyribosomes, RNA Caps, Cell Hypoxia, RNA-Binding Proteins, 3' Untranslated Regions, RNA Cap-Binding Proteins, Eukaryotic Initiation Factor-4E, Cell Line, Tumor, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, ErbB Receptors
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