A role for AKT1 in nonsense-mediated mRNA decay

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


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


  • 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