ArticlePLoS biology2013
The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
Article in PLoS biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 55 citations in OpenAlex.
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- Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.International journal of molecular sciences · 2025Review
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- Translational control of murine adiponectin expression by an upstream open reading frame element.RNA biology · 2023Article
- VEGFR1 signaling in retinal angiogenesis and microinflammation.Progress in retinal and eye research · 2021Review
- The regulation of protein translation and its implications for cancer.Signal transduction and targeted therapy · 2021Review
- LncRNA NR038975, A Serum-Based Biomarker, Promotes Gastric Tumorigenesis by Interacting With NF90/NF45 Complex.Frontiers in oncology · 2021Article
- Crucial roles of different RNA-binding hnRNP proteins in Stem Cells.International journal of biological sciences · 2021Review
- Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins.Frontiers in immunology · 2021Review
- Glutamyl-Prolyl-tRNA Synthetase Regulates Proline-Rich Pro-Fibrotic Protein Synthesis During Cardiac Fibrosis.Circulation research · 2020Article
- Muscleblind-like 2 controls the hypoxia response of cancer cells.RNA (New York, N.Y.) · 2020Article
- Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.OncoTargets and therapy · 2020Article
- hnRNP L-mediated RNA switches function as a hypoxia-induced translational regulon.Biochemical and biophysical research communications · 2019Article
- Mammalian RNA switches: Molecular rheostats in gene regulation, disease, and medicine.Computational and structural biotechnology journal · 2019Review
- Coupling Green Fluorescent Protein Expression with Chemical Modification to Probe Functionally Relevant Riboswitch Conformations in Live Bacteria.Biochemistry · 2018Article
- The GAIT translational control system.Wiley interdisciplinary reviews. RNA · 2018Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, condition-dependent responses. Here, we elucidate the components and mechanisms driving a protein-directed RNA switch in the 3'UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel HILDA (hypoxia-inducible hnRNP L-DRBP76-hnRNP A2/B1) complex that coordinates a three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia and inflammation. In addition to binding the CA-rich element (CARE), heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates switch assembly and function. hnRNP L undergoes two previously unrecognized, condition-dependent posttranslational modifications: IFN-γ induces prolyl hydroxylation and von Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas hypoxia stimulates hnRNP L phosphorylation at Tyr(359), inducing binding to hnRNP A2/B1, which stabilizes the protein. Also, phospho-hnRNP L recruits DRBP76 (double-stranded RNA binding protein 76) to the 3'UTR, where it binds an adjacent AU-rich stem-loop (AUSL) element, "flipping" the RNA switch by disrupting the GAIT (interferon-gamma-activated inhibitor of translation) element, preventing GAIT complex binding, and driving robust VEGFA mRNA translation. The signal-dependent, HILDA complex coordinates the function of a trio of neighboring RNA elements, thereby regulating translation of VEGFA and potentially other mRNA targets. The VEGFA RNA switch might function to ensure appropriate angiogenesis and tissue oxygenation during conflicting signals from combined inflammation and hypoxia. We propose the VEGFA RNA switch as an archetype for signal-activated, protein-directed, multi-element RNA switches that regulate posttranscriptional gene expression in complex environments.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.