A stress-responsive RNA switch regulates VEGFA expression


Ligand binding to structural elements in the non-coding regions of messenger RNA modulates gene expression1,2. Ligands such as free metabolites or other small molecules directly bind and induce conformational changes in regulatory RNA elements known as riboswitches1,2,3,4. Other types of RNA switches are activated by complexed metabolites—for example, RNA-ligated metabolites such as aminoacyl-charged transfer RNA in the T-box system5, or protein-bound metabolites in the glucose- or amino-acid-stimulated terminator-anti-terminator systems6,7. All of these switch types are found in bacteria, fungi and plants8,9,10. Here we report an RNA switch in human vascular endothelial growth factor-A (VEGFA, also known as VEGF) mRNA 3′ untranslated region (UTR) that integrates signals from interferon (IFN)-γ and hypoxia to regulate VEGFA translation in myeloid cells. Analogous to riboswitches, the VEGFA 3′ UTR undergoes a binary conformational change in response to environmental signals. However, the VEGFA 3′ UTR switch is metabolite-independent, and the conformational change is dictated by mutually exclusive, stimulus-dependent binding of proteins, namely, the IFN-γ-activated inhibitor of translation complex11,12 and heterogeneous nuclear ribonucleoprotein L (HNRNPL, also known as hnRNP L). We speculate that the VEGFA switch represents the founding member of a family of signal-mediated, protein-dependent RNA switches that evolved to regulate gene expression in multicellular animals in which the precise integration of disparate inputs may be more important than the rapidity of response.

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Figure 1: Suppression of GAIT-mediated translation silencing of VEGFA by hypoxia.
Figure 2: HNRNPL binding to HSR restores VEGFA translation in hypoxia.
Figure 3: HNRNPL is regulated by stimulus-dependent proteasomal degradation.
Figure 4: Protein-dependent switching of the VEGFA 3′ UTR HSR.


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We are grateful to D. Driscoll and T. M. Henkin for helpful discussions. This work was supported by National Institutes of Health grants P01 HL29582, R01 HL67725 and P01 HL76491 (to P.L.F.), and R01 DK60596 (to M.H.).

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Correspondence to Paul L. Fox.

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Ray, P., Jia, J., Yao, P. et al. A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 915–919 (2009). https://doi.org/10.1038/nature07598

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