The HILDA Complex Coordinates a Conditional Switch in the 3′-Untranslated Region of the VEGFA mRNA

• DOI: 10.1371/journal.pbio.1001635
• Publication Date: 2013-08-21T00:52:33Z
• Authors: Peng Yao; Alka A. Potdar; Partho Sarothi Ray; Sandeepa M. Eswar...; Andrew C. Flagg; Belinda Willard; Paul L. Fox
• Keywords: Vascular Endothelial Growth Factor A; 0303 health sciences; QH301-705.5; Reverse Transcriptase Polymerase Chain Reaction; Ubiquitination; Fluorescent Antibody Technique; Mass Spectrometry; Cell Line; 3. Good health; 03 medical and health sciences; Heterogeneous-Nuclear Ribonucleoprotein L; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Mutagenesis, Site-Directed; Humans; RNA, Messenger; Biology (General); Nuclear Factor 90 Proteins; 3' Untranslated Regions; Research Article

Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, condition-dependent responses. Here, we elucidate the components mechanisms driving a protein-directed RNA switch in 3'UTR of vascular endothelial growth factor (VEGF)-A. We describe novel HILDA (hypoxia-inducible hnRNP L-DRBP76-hnRNP A2/B1) complex that coordinates three-element switch, enabling VEGFA mRNA translation during combined hypoxia inflammation. In addition binding CA-rich element (CARE), heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates assembly function. undergoes two previously unrecognized, posttranslational modifications: IFN-γ induces prolyl hydroxylation von Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas stimulates phosphorylation at Tyr(359), inducing A2/B1, which stabilizes protein. Also, phospho-hnRNP recruits DRBP76 (double-stranded protein 76) 3'UTR, where it binds an adjacent AU-rich stem-loop (AUSL) element, "flipping" by disrupting GAIT (interferon-gamma-activated inhibitor translation) preventing binding, robust translation. The signal-dependent, function trio neighboring elements, thereby regulating potentially other targets. might ensure appropriate angiogenesis tissue oxygenation conflicting signals from inflammation hypoxia. propose as archetype for signal-activated, protein-directed, multi-element switches regulate posttranscriptional gene expression environments.