The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.

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. W...

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Autores principales:	Peng Yao, Alka A Potdar, Partho Sarothi Ray, Sandeepa M Eswarappa, Andrew C Flagg, Belinda Willard, Paul L Fox
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6184c638a0c14254a7434832fc301adc
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spelling	oai:doaj.org-article:6184c638a0c14254a7434832fc301adc2021-11-18T05:37:52ZThe HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.1544-91731545-788510.1371/journal.pbio.1001635https://doaj.org/article/6184c638a0c14254a7434832fc301adc2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23976881/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Cell 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.Peng YaoAlka A PotdarPartho Sarothi RaySandeepa M EswarappaAndrew C FlaggBelinda WillardPaul L FoxPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 8, p e1001635 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Peng Yao Alka A Potdar Partho Sarothi Ray Sandeepa M Eswarappa Andrew C Flagg Belinda Willard Paul L Fox The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
description	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.
format	article
author	Peng Yao Alka A Potdar Partho Sarothi Ray Sandeepa M Eswarappa Andrew C Flagg Belinda Willard Paul L Fox
author_facet	Peng Yao Alka A Potdar Partho Sarothi Ray Sandeepa M Eswarappa Andrew C Flagg Belinda Willard Paul L Fox
author_sort	Peng Yao
title	The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
title_short	The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
title_full	The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
title_fullStr	The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
title_full_unstemmed	The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.
title_sort	hilda complex coordinates a conditional switch in the 3'-untranslated region of the vegfa mrna.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/6184c638a0c14254a7434832fc301adc
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The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.

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