A stress-responsive RNA switch regulates VEGF expression

Ligand binding to structural elements in noncoding regions of mRNA 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 riboswitches1-4. Other types of RNA switches are activated by complexed metabolites, e.g., RNA-ligated metabolites such as aminoacyl-charged tRNA in the T-box system5, or protein-bound metabolites in the glucose- or amino acid-stimulated terminator-antiterminator systems6,7. All of these switch types are found in bacteria, fungi, and plants8-10. Here, we report an RNA switch in human vascular endothelial growth factor-A (VEGF) mRNA 3’UTR that integrates signals from interferon (IFN)-γ and hypoxia to regulate VEGF translation in myeloid cells. Analogous to riboswitches, the VEGF 3’UTR undergoes a binary conformational change in response to environmental signals. However, the VEGF 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 (GAIT) complex11,12 and heterogenous nuclear ribonucleoprotein (hnRNP) L. We speculate the VEGF switch represents the founding member of a family of signal-mediated, protein-dependent RNA switches that evolved to regulate gene expression in multicellular animals where precise integration of disparate inputs may be more important than rapidity of response.