A role for AKT1 in nonsense-mediated mRNA decay

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

doi:10.1093/nar/gkab882

A role for AKT1 in nonsense-mediated mRNA decay

Nucleic Acids Res. 2021 Nov 8;49(19):11022-11037. doi: 10.1093/nar/gkab882.

Authors

Martine Palma^{1

2}, Catherine Leroy^{1

2}, Sophie Salomé-Desnoulez³, Elisabeth Werkmeister^{3

4}, Rebekah Kong^{1

2}, Marc Mongy³, Hervé Le Hir⁵, Fabrice Lejeune^{1

2}

Affiliations

¹ Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France.
² Unité tumorigenèse et résistance aux traitements, Institut Pasteur de Lille, F-59000 Lille, France.
³ Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UMS 2014 - PLBS, F-59000 Lille, France.
⁴ Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - center for Infection and Immunity of Lille, F-59000 Lille, France.
⁵ Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 46 rue d'Ulm, 75005 Paris, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Codon, Nonsense*
Eukaryotic Initiation Factor-4E / genetics
Eukaryotic Initiation Factor-4E / metabolism
Gene Library
Genes, Reporter
HEK293 Cells
HeLa Cells
Humans
Luciferases / genetics
Luciferases / metabolism
Nonsense Mediated mRNA Decay*
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
RNA Helicases / genetics*
RNA Helicases / metabolism
RNA, Messenger / genetics*
RNA, Messenger / metabolism
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism
Signal Transduction
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
Trans-Activators / genetics*
Trans-Activators / metabolism

Substances

Codon, Nonsense
Eukaryotic Initiation Factor-4E
RNA, Messenger
RNA-Binding Proteins
Trans-Activators
UPF3A protein, human
Luciferases
MTOR protein, human
AKT1 protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
RNA Helicases
UPF1 protein, human