Type I arginine methyltransferases are intervention points to unveil the oncogenic Epstein-Barr virus to the immune system - Archive ouverte HAL Access content directly
Journal Articles Nucleic Acids Research Year : 2022

Type I arginine methyltransferases are intervention points to unveil the oncogenic Epstein-Barr virus to the immune system

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Rodrigo Prado Martins

Abstract

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 GArbased 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.
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Dates and versions

hal-03887312 , version 1 (06-12-2022)

Licence

Attribution - CC BY 4.0

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Cite

Gaelle Angrand, Alicia Quillévéré, Nadège Loaëc, Van-Trang Dinh, Ronan Le Sénéchal, et al.. Type I arginine methyltransferases are intervention points to unveil the oncogenic Epstein-Barr virus to the immune system. Nucleic Acids Research, 2022, 50 (20), pp.11799-11819. ⟨10.1093/nar/gkac915⟩. ⟨hal-03887312⟩
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