1. Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
2. Department of Biology, Indian Institute of Science Education and Research, Kolkata 700106, India
3. Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA

Correspondence to: Paul L. Fox¹ Correspondence and requests for materials should be addressed to P.L.F. (Email: foxp@ccf.org).

Abstract

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, 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 systems^{6, 7}. All of these switch types are found in bacteria, fungi and plants^{8, 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)- 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--activated inhibitor of translation complex^{11, 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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