Molecular mechanisms of recruitment, function and regulation of UPF1 in histone mRNA decay

Animal replication-dependent histone mRNAs end in a conserved stem loop (SL) instead of the canonical poly(A) tail present in all other eukaryotic mRNAs. Degradation of the histone SL at the end of the S-phase is initiated by the stem-loop binding protein SLBP and its interplay with the RNA helicase UPF1 and the exoribonuclease 3’hExo. We report direct interactions between SLBP and UPF1 and show that the unstructured SLBP N-terminus wraps around the UPF1 helicase core, contacting it at multiple sites. Although binding of SLBP to UPF1 impedes unwinding activity, it is critical for efficient histone mRNA decay in cells, as unwinding of the SL facilitates degradation by 3’hExo. Here we show that the UPF1-activator, UPF2, binds 3’hExo, and that UPF2-mediated activation of UPF1 overrides the inhibitory effect of SLBP. Our results highlight the intricate network of UPF1-centric protein-protein and protein/RNA interactions that fine-tunes its unwinding activity and orchestrates timely and efficient degradation of histone mRNA.