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

María José Lista (1) , Rodrigo Prado Martins (2) , Olivier Billant (1) , Marie-Astrid Contesse (1) , Sarah Findakly (2) , Pierre Pochard (3) , Chrysoula Daskalogianni (2) , Claire Beauvineau (4) , Corinne Guetta (4) , Christophe Jamin (3) , Marie-Paule Teulade-Fichou (4) , Robin Fahraeus (2) , Cécile Voisset (1) , Marc Blondel (1)

1 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
2 U1162 - Génomique Fonctionnelle des Tumeurs Solides
3 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies
4 Chimie, Modélisation et Imagerie pour la Biologie [Orsay]

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.

Mots clés: maintenance protein EBNA1; Epstein-Barr virus; mRNA

Mots clés: immune evasion

Domaines: Sciences du Vivant [q-bio]

María José Lista, Rodrigo Prado Martins, Olivier Billant, Marie-Astrid Contesse, Sarah Findakly, et al.. Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA1 mRNA. Nature Communications, 2017, 8 (1), pp.14 - 27. ⟨10.1038/ncomms16043⟩. ⟨hal-01682747⟩