No

Nucleolin is involved in Epstein-Barr virus EBNA1- based mechanism of immune evasion and represents a relevant therapeutic target to treat cancers linked to this virus

• Auteur / Autrice : Maria José Lista
• Direction : Marc Blondel, Cécile Voisset
• Type : Thèse de doctorat
• Discipline(s) : Biologie santé
• Date : Soutenance le 07/12/2016
• Etablissement(s) : Brest
• Ecole(s) doctorale(s) : École doctorale Santé, information-communication et mathématiques, matière (Brest, Finistère)
• Partenaire(s) de recherche : Laboratoire : Génétique, génomique fonctionnelle et biotechnologies (Brest, Finistère)
• Jury : Président / Présidente : Vianney Pichereau
• Jury : Examinateurs / Examinatrices : Marc Blondel, Cécile Voisset, Vianney Pichereau, Évelyne Manet, Hervé Prats, Robin Fåhraeus, Laurent Meijer, Marie-Paule Teulade-Fichou
• Jury : Rapporteur / Rapporteuse : Évelyne Manet, Hervé Prats

Mots clés

Mots clés contrôlés

Cancer -- Thérapeutique

Nucléoles

Virus d'Epstein-Barr

Mots clés libres

Epstein-Barr Virus

Nucléoline

Cancer

Epstein-Barr Virus

Nucleolin

Cancer

Résumé

No.

The Epstein-Barr Virus (EBV) is the first oncogenic virus described in humans. It is a ubiquitous virus which infects over 90% of the human population. EBV causes a latent infection of B lymphocytes and remains asymptomatic in most of infected individuals. However, insome conditions like immunosuppression, EBV can cause uncontrolled cell proliferation responsible for some types of cancers like Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma. During latency, EBNA1 is the only protein expressed in all EBV-infected cells as it is essential for EBV genome replication and maintenance. EBNA1 is highly antigenic and T cells raised against EBNA1 exist ; nevertheless EBV-infected cells are not eliminated by the host immune system. This is due to the central GAr (Gly-Ala repeat) domain of EBNA1 which is able to inhibit the translation of its own mRNA in cis, there by preventing the recognition of EBV-infected cells by the immunesystem of the host. The mechanisms involved in this GAr-based translation inhibition were unknown when I started my PhD. During this thesis, we identified the first cellular factor, Nucleolin (NCL), able to affect GAr-based translation inhibition. We showed that NCL over expression enhances EBNA1 translation inhibition and inversely, that its down regulation decreases EBNA1 translation inhibition effect. Furthermore, we demonstrated that the interaction between NCL and GArRNA occurs throught NCL binding to GAr-encoding mRNA via a particular secondary structure called G-quadruplex (G4).We showed that disrupting NCL-GAr RNA interaction with small G4 ligands enhances EBNA1 translation and thus antigen presentation, which constitutes a new therapeutic avenue to treat EBV-associated cancers. Finally, we went deeper into the mechanism involved in this interaction by showing that NCL has a direct effect on the GAr-based translation inhibition and that the nuclear location of NCL-GAr RNA interaction is forced by the nuclear location of NCL in the cells. Taken together, these results have shed light upon the mechanism involved in the GAr domain translation inhibition and immune evasion, and have revealed a possible therapeutic target to eradicate EBV-associated cancers.