A role for AKT1 in nonsense-mediated mRNA decay.

Martine Palma,Elisabeth Werkmeister,Hervé Le Hir,Rebekah Kong,Catherine Leroy,Fabrice Lejeune,Sophie Salomé-Desnoulez,Marc Mongy

doi:10.1093/nar/gkab882

Abstract

Nonsense-mediated mRNA decay (NMD) is a highly regulated quality control mechanism through which mRNAs harboring a premature termination codon are degraded. It is also a regulatory pathway for some genes. This mechanism is subject to various levels of regulation, including phosphorylation. To date only one kinase, SMG1, has been described to participate in NMD, by targeting the central NMD factor UPF1. Here, screening of a kinase inhibitor library revealed as putative NMD inhibitors several molecules targeting the protein kinase AKT1. We present evidence demonstrating that AKT1, a central player in the PI3K/AKT/mTOR signaling pathway, plays an essential role in NMD, being recruited by the UPF3X protein to phosphorylate UPF1. As AKT1 is often overactivated in cancer cells and as this should result in increased NMD efficiency, the possibility that this increase might affect cancer processes and be targeted in cancer therapy is discussed.

Highlights

Quality controls occur at different steps in gene expression
UPF1 phosphorylation at the Threonine 28 promotes the recruitment of SMG6, while phosphorylation of the Serine 1096 induces the recruitment of SMG5/SMG7 to nonsense-mediated mRNA decay (NMD) mRNP targets, causing departure of the ribosome paused on the premature termination codon (PTC) and activation of mRNA decay pathways [6,13,14]
AKT is a kinase involved in the PI3K/AKT/mTOR signaling pathway

Summary

Introduction

Quality controls occur at different steps in gene expression One such control is nonsense-mediated mRNA decay (NMD), which prevents the synthesis of potentially deleterious truncated proteins by targeting mRNAs carrying a premature termination codon (PTC) [1,2,3,4]. UPF1 and UPF2 are phosphoproteins [5,6] Phosphorylation of both proteins is required for NMD activation, and this suggests that kinases involved in their phosphorylation may regulate NMD. UPF1 phosphorylation at the Threonine 28 promotes the recruitment of SMG6, while phosphorylation of the Serine 1096 induces the recruitment of SMG5/SMG7 to NMD mRNP targets, causing departure of the ribosome paused on the PTC and activation of mRNA decay pathways [6,13,14]. As UPF2 is a phosphoprotein [5,19] and as no UPF2-phosphorylating kinase has been identified in vivo, it is strongly expected that additional kinases are involved in NMD

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Conclusion