Ago2/miRISC-mediated inhibition of CBP80/20-dependent translation and thereby abrogation of nonsense-mediated mRNA decay require the cap-associating activity of Ago2

Nuclear cap-binding protein (CBP) 80/20-dependent translation (CT) is one of the targets for miRNA-mediated gene silencing. Here, we provide evidence that human argonaute 2 (Ago2) competes with CBP80/20 for cap-association, inhibiting CT and thus nonsense-mediated mRNA decay (NMD), which is tightly coupled to CT. Tethering of Ago2, but not of Ago2F2V2 which lacks cap-association activity, to the 3′UTR of PTC-containing mRNA abrogates NMD. Immunoprecipitation using CBP80 antibody reveals that Ago2, but not Ago2F2V2, inhibits the binding of CBP80/20 to cap structure. Our observations provide molecular insight into the cross-talk between miRNA-mediated gene silencing, CT, and NMD.Structured summary of protein interactionsAGO2 physically interacts with GW182 by anti tag coimmunoprecipitation (View interaction)

► NMD is abrogated by tethering of Ago2 to the 3′UTR of PTC-containing mRNA.
► Introduction of F2V2 substitutions abolishes cap-associating activity of Ago2.
► Ago2 inhibits the binding of CBP80/20 to the cap structure.