Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA1 mRNA

María José Lista, Rodrigo Prado Martins, Olivier Billant, Marie-Astrid Contesse, Sarah Findakly, Pierre Pochard, Chrysoula Daskalogianni, Claire Beauvineau, Corinne Guetta, Christophe Jamin, Marie-Paule Teulade-Fichou, Robin Fåhraeus, Cécile Voisset and Marc Blondel ()
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María José Lista: Institut National de la Santé et de la Recherche Médicale UMR1078; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire
Rodrigo Prado Martins: Cibles Thérapeutiques, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire
Olivier Billant: Institut National de la Santé et de la Recherche Médicale UMR1078; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire
Marie-Astrid Contesse: Institut National de la Santé et de la Recherche Médicale UMR1078; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire
Sarah Findakly: Cibles Thérapeutiques, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire
Pierre Pochard: Inserm UMR 1227, Lymphocytes B et Autoimmunité; CHRU Brest, Hôpital Morvan, Laboratoire d’Immunologie
Chrysoula Daskalogianni: Cibles Thérapeutiques, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire
Claire Beauvineau: Chemistry, Modelling and Imaging for Biology, CNRS UMR9187 - Inserm U1196, Institut Curie, Université Paris-Sud
Corinne Guetta: Chemistry, Modelling and Imaging for Biology, CNRS UMR9187 - Inserm U1196, Institut Curie, Université Paris-Sud
Christophe Jamin: Inserm UMR 1227, Lymphocytes B et Autoimmunité; CHRU Brest, Hôpital Morvan, Laboratoire d’Immunologie
Marie-Paule Teulade-Fichou: Chemistry, Modelling and Imaging for Biology, CNRS UMR9187 - Inserm U1196, Institut Curie, Université Paris-Sud
Robin Fåhraeus: Cibles Thérapeutiques, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire
Cécile Voisset: Institut National de la Santé et de la Recherche Médicale UMR1078; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire
Marc Blondel: Institut National de la Santé et de la Recherche Médicale UMR1078; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1, which is essential for viral genome maintenance but highly antigenic. EBV has seemingly evolved a system in which the mRNA sequence encoding the glycine-alanine repeats (GAr) of the EBNA1 protein limits its expression to the minimal level necessary for function while minimizing immune recognition. Here, we identify nucleolin (NCL) as a host factor required for this process via a direct interaction with G-quadruplexes formed in GAr-encoding mRNA sequence. Overexpression of NCL enhances GAr-based inhibition of EBNA1 protein expression, whereas its downregulation relieves the suppression of both expression and antigen presentation. Moreover, the G-quadruplex ligand PhenDC3 prevents NCL binding to EBNA1 mRNA and reverses GAr-mediated repression of EBNA1 expression and antigen presentation. Hence the NCL-EBNA1 mRNA interaction is a relevant therapeutic target to trigger an immune response against EBV-carrying cancers.

Date: 2017
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DOI: 10.1038/ncomms16043

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