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Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD

Pavel V Ivanov1, Niels H Gehring, Joachim B Kunz

  • 1Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.

The EMBO Journal
|February 8, 2008
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) controls gene expression. UPF1 protein halts translation termination, and its interaction with the exon junction complex (EJC) activates NMD, integrating models of mRNA surveillance.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial cellular surveillance pathway regulating mRNA expression.
  • UPF1 protein phosphorylation during translation termination is key to NMD pathway activation.
  • Existing models for NMD mechanisms require integration to fully explain pathway regulation.

Purpose of the Study:

  • To elucidate the role of UPF1 in translation termination and its interaction with other factors in NMD.
  • To investigate the interplay between UPF1, PABPC1, and the EJC in regulating NMD.
  • To propose an integrated model for NMD activation.

Main Methods:

  • Investigated protein-protein interactions between UPF1, eRF1, eRF3, PABPC1, and EJC components (UPF2, UPF3b).
  • Utilized mutation studies to assess the functional significance of UPF1 interactions.
  • Developed a mechanistic model integrating experimental findings.

Main Results:

  • UPF1 inhibits translation termination, while PABPC1 stimulates it.
  • UPF1 interacts with eRF1 and eRF3 (GTP- and GDP-bound states).
  • UPF1 interacts with the EJC via UPF2 or UPF3b, leading to UPF1 phosphorylation and NMD activation.

Conclusions:

  • UPF1 halts translation termination, becoming phosphorylated by SMG1 when PABPC1 interaction is hindered.
  • The EJC, using UPF2 or UPF3b, influences termination via UPF1.
  • This provides an integrated model for NMD, explaining alternative pathway mechanisms.

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