Fig 1: Model. The interaction between NCL and G4 of EBNA1 mRNA is direct and the C-terminal RGG motif of NCL is required for both the ability of NCL to interact with G4 that form in the GAr-encoding sequence of EBNA1 mRNA and for NCL’s crucial role in GAr-based inhibition of translation, the molecular mechanism at the root of EBNA1 immune evasion. RGG motifs are the main substrates of type I PRMTs. The interaction between NCL and G4 of EBNA1 mRNA, as well as the GAr-based inhibition of translation and EBNA1 immune evasion, depend on type I PRMTs, in particular PRMT1. Results of the site-directed mutagenesis of the arginines of the RGG motif of NCL experiments suggest that the role of type I PRMTs in EBNA1 immune evasion involves methylation of the arginines of the RGG motif of NCL. Hence, two possible models for the role RGG methylation by type I PRMTs in EBNA1 evasion can be envisaged: direct (A) or indirect (B). In the direct model (A), the methylation of arginines of the RGG motif of NCL would directly favour the interaction of the latter with G4 of EBNA1 mRNA and therefore the inhibition of its translation, which in turn allows EBNA1 and EBV to evade the immune system. In the indirect model (B), the non-methylated RGG motif of NCL would be sequestered by a protein partner [protein X, which may be nucleolin itself or another protein such as the various ribosomal proteins which have been shown to interact with the RGG motif of NCL (62)], thereby preventing its interaction with G4 of EBNA1 mRNA. In this model, methylation of the arginines of the RGG motif would interfere with its interaction with protein X, thus releasing NCL and allowing its RGG motif to interact with G4 of EBNA1 mRNA. Our in vitro assays did not show any significant difference between methylated and unmethylated RGG for the binding of EBNA1 mRNA G4, suggesting the indirect role is the most likely.
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