A stress-responsive RNA switch regulates VEGFA expression

Abstract

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.

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

“…In a well-studied example, hnRNPL stabilizes VEGF-A mRNA through binding to a CA-rich element in the VEGF-A 3′ UTR (36,37). Two mechanisms for this phenomenon have been documented: a riboswitch-like mechanism involving mutually exclusive binding of hnRNPL and the GAIT complex (37), and the ability of hnRNPL to block binding of miRNAs to the 3′ UTR (36) (reviewed in ref. 38).…”

Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth neuropathy

“…Rather, CMT-associated mutations in aminoacyl-tRNA synthetases might disrupt noncanonical functions of these proteins, or result in a dominant ''gain of toxic function.'' Commonly, expanded functions of tRNA synthetases, including those for tyrosyl-tRNA synthetase, are activated by alternative splicing, proteolysis, or post-translational modification, and act on extracellular or intracellular targets (28)(29)(30). An expanded function of human TyrRS in endothelial cells was mutationally separated from that for aminoacylation, that is, mutations were isolated that disrupted cell signaling, but not aminoacylation, and vice versa (31).…”

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

“…During hypoxia, this conformational switch in the VEGFA 3 0 UTR overrides the repressive effect of the GAIT complex allowing high levels of VEGFA translation. 39 To gain further insight into the post-transcriptional regulation of VEGFA mRNA in our system, biotinylated DNA oligomers complementary to the VEGFA mRNA were used to pull down bound RBPs (Fig. 3).…”