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A role for AKT1 in nonsense-mediated mRNA decay

Martine Palma1,2, Catherine Leroy1,2, Sophie Salomé-Desnoulez3

  • 1Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France.

Nucleic Acids Research
|October 11, 2021
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) is regulated by AKT1, a protein kinase. AKT1 phosphorylates UPF1, impacting mRNA quality control and potentially cancer processes.

Area of Science:

  • Molecular Biology
  • Cellular Regulation
  • Biochemistry

Background:

  • Nonsense-mediated mRNA decay (NMD) is a critical cellular surveillance pathway that degrades aberrant mRNAs with premature termination codons.
  • Phosphorylation is a key regulatory mechanism in NMD, with SMG1 previously identified as the sole kinase targeting the UPF1 protein.
  • The precise regulatory network governing NMD phosphorylation remains incompletely understood.

Purpose of the Study:

  • To identify novel kinases involved in NMD regulation.
  • To investigate the role of the AKT1 kinase in the NMD pathway.
  • To explore the implications of AKT1-mediated NMD regulation in cancer.

Main Methods:

  • Screening of a kinase inhibitor library to identify NMD modulators.
  • Biochemical assays to confirm kinase activity and substrate interactions.
  • Cellular recruitment studies to elucidate protein-protein interactions within the NMD complex.

Main Results:

  • Kinase inhibitors targeting AKT1 were identified as potent NMD inhibitors.
  • AKT1 was demonstrated to be recruited by UPF3X and to phosphorylate UPF1, a central NMD factor.
  • Evidence suggests AKT1 plays an essential role in NMD regulation.

Conclusions:

  • AKT1 is a novel and essential kinase in the nonsense-mediated mRNA decay pathway.
  • AKT1-mediated phosphorylation of UPF1 highlights a new regulatory axis in mRNA quality control.
  • The frequent overactivation of AKT1 in cancer suggests a potential link between enhanced NMD and tumorigenesis, offering new therapeutic avenues.

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