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 maintenance but is also highly antigenic. Hence, EBV seemingly evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA to the minimal level to ensure its essential function, thereby, at the same time, minimizing immune recognition. Therefore, defining intervention points at which to interfere with GAr-based inhibition of translation is an important step to trigger an immune response against EBV-carrying cancers. The host protein nucleolin (NCL) plays a critical role in this process via a direct interaction with G-quadruplexes (G4) formed in the GAr-encoding sequence of the viral EBNA1 mRNA. Here we show that the C-terminal arginine-glycine-rich (RGG) motif of NCL is crucial for its role in GAr-based inhibition of translation by mediating interaction of NCL with G4 of EBNA1 mRNA. We also show that this interaction depends on the type I arginine methyltransferase family, notably PRMT1 and PRMT3: drugs or small interfering RNA that target these enzymes prevent efficient binding of NCL on G4 of EBNA1 mRNA and relieve GAr-based inhibition of translation and of antigen presentation. Hence, this work defines type I arginine methyltransferases as therapeutic targets to interfere with EBNA1 and EBV immune evasion.

Chemistry and Modelling for the Biology of Cancer CNRS UMR9187 Inserm U1196 Institut Curie Université Paris Saclay Orsay Campus universitaire Bat 110 F 91405 France

Cibles Thérapeutiques Institut National de la Santé et de la Recherche Médicale UMR1162 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis 27 rue Juliette Dodu F 75010 Paris France

Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang Bretagne; CHRU Brest Hôpital Morvan Laboratoire de Génétique Moléculaire 22 avenue Camille Desmoulins F 29200 Brest France

ISP INRAE Université de Tours UMR1282 Tours Nouzilly France

RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

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