Marc Blondel, Univ Brest, Inserm, EFS, UMR 1078,Genetics, Functional Genomics and Biotechnology, France

Nucleolin directly mediates Epstein-Barr virus (EBV) immune evasion through binding to G-quadruplexes of EBNA1 mRNA thus defining new therapeutic targets to unveil EBV-related cancers to the immune system

The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome replication and maintenance but also highly antigenic and CD8+ T cells directed towards EBNA1 epitopes exist in all infected individuals. Hence, EBV evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA at a minimal level to ensure its essential function thereby, at the same time, minimizing immune recognition. Defining intervention points where to interfere with EBNA1 immune evasion is an important step to trigger an immune response against EBV-carrying cancers. We recently developed a yeast-based assay that recapitulates all the aspects of EBNA1 self-limitation of expression and that allowed us to isolate compounds that interfere with EBNA1 stealthiness, thereby validating the yeast assay¹. Thanks to this assay, we also recently uncovered the role of the host cell nucleolin (NCL) in this process via a direct interaction of this protein with G-quadruplexes (G4) formed in GAr-encoding sequence of EBNA1 mRNA^2,3. In addition, the benchmark G4 ligand PhenDC3 prevents NCL binding on EBNA1 mRNA and reverses GAr-mediated repression of translation and antigen presentation². This shows that the NCL-EBNA1 mRNA interaction is a relevant therapeutic target to unveil EBV-carrying cancers to the immune system³. Finally, thanks to a structure-activity relationship study we isolated new patentable G4 ligands that are more active and less toxic than PhenDC3⁴.

1. C Voisset et al Disease Models & Mechanisms 2014, 7: 435-444
2. MJ Lista et al Nature Communications 2017, 8: 16043
3. MJ Lista et al Microbial Cell 2017, 4: 305-7
4. O Reznichenko et al European J of Medicinal Chemistry 2019, 178: 13-29

Host: Associate Professor Victoria Birkedal, iNANO & Dept. of Chemistry, AU