A stress-responsive RNA switch regulates VEGFA expression

Ligand binding to structural elements in the non- coding regions of messenger RNA modulates gene expression(1,2). Ligands such as free metabolites or other small molecules directly bind and induce conformational changes in regulatory RNA elements known as riboswitches(1-4). 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 system(5), or protein-bound metabolites in the glucose- or amino- acid- stimulated terminator-anti- terminator systems(6,7). All of these switch types are found in bacteria, fungi and plants(8-10). Here we report an RNA switch in human vascular endothelial growth factor- A ( VEGFA, also known as VEGF) mRNA 39 untranslated region ( UTR) that integrates signals from interferon ( IFN)-gamma 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-gamma-activated inhibitor of translation complex(11,12) and heterogeneous