A stress-responsive RNA switch regulates VEGFA expression

Open Access
Publisher Website
Google Scholar
Abstract
RNA switches or riboswitches, involving the binding of small ligands to RNAs, are known to regulate gene expression in bacteria, fungi and plants, where they frequently respond to a deficit or excess of various metabolites or nutrients. Now an RNA switch has been identified in human cells. It is an element in the 3′ untranslated region of the mRNA encoding vascular endothelial growth factor (VEGF), a protein critical for blood vessel formation. The switchable mRNA can bind two different complexes, GAIT or hnRNP L. The binding of one induces a specific conformation that precludes binding of the other. Which factor is bound depends on environmental signals indicating inflammatory and hypoxic status. The switch may have evolved to maintain delivery of oxygen to hypoxic, inflammatory tissues, and may be an example of a type of protein-dependent RNA switch evolved to regulate gene expression in multicellular animals where the precise integration of disparate inputs is more important than a rapid response. The binding of small ligands to RNAs is a mechanism for regulation of gene expression in bacteria, fungi and plants. This work describes the first RNA switch to be identified in human cells. This element in the 3′ UTR of the VEGFA mRNA can bind two different complexes, GAIT or HNRNPL. The binding of one induces a specific conformation that precludes binding of the other. Which factor is bound depends on environmental signals indicating inflammatory and hypoxic status. 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.