Editors' ChoiceTranslational Regulation

Stress Flips the Switch

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Science Signaling  17 Feb 2009:
Vol. 2, Issue 58, pp. ec60
DOI: 10.1126/scisignal.258ec60

Under hypoxic conditions, cells respond by increasing the expression of genes, such as vascular endothelial growth factor-A (VEGFA), whose products help the cells adapt to the scarcity of oxygen. Hypoxic environments often also contain proinflammatory factors, such as interferon-γ (IFN-γ), which inhibits translation of VEGFA mRNA in an IFN-γ–activated inhibitor of translation complex (GAIT)–dependent mechanism. Thus, cells must balance the opposing effects of these stimuli on VEGFA expression. Ray et al. investigated how U937 monocytic cells responded to simultaneous exposure to hypoxia and IFN-γ. Western blotting analysis showed that, whereas IFN-γ reduced the abundance of VEGFA under normoxia, it failed to do so under hypoxia. Analysis of polysomes and reverse transcription polymerase chain reaction (RT-PCR) assays demonstrated that hypoxia blocked IFN-γ–mediated silencing of VEGFA mRNA translation. Lysates from IFN-γ–treated normoxic, but not hypoxic, cells blocked translation of a reporter transcript consisting of the hypoxia stability region (HSR), part of the 3′ untranslated region of VEGFA mRNA. As well as containing a GAIT element, the HSR is also bound by HNRNPL, a protein that stabilizes VEGFA mRNA. Ultraviolet-crosslinking and immunodepletion experiments showed binding of the GAIT protein EPRS to the HSR under normoxia and binding of HNRNPL under hypoxia. Analysis of the secondary structure of HSR showed that it adopted a translation-permissive conformation in the presence of IFN-γ and hypoxia and a translation-silencing conformation in the presence of IFN-γ alone. The mutually exclusive binding of either GAIT or HNRNPL switched the HSR between these conformations. This study is the first to demonstrate an RNA switch in humans; in contrast to the RNA switches of bacteria, fungi, and plants that respond to metabolites or nutrients, this human switch is protein dependent.

P. S. Ray, J. Jia, P. Yao, M. Majumder, M. Hatzoglou, P. L. Fox, A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 915–919 (2009). [PubMed]

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