Eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay by two genetically separable mechanisms

PLoS One. 2014 Aug 22;9(8):e104391. doi: 10.1371/journal.pone.0104391. eCollection 2014.


Nonsense-mediated mRNA decay (NMD), which is best known for degrading mRNAs with premature termination codons (PTCs), is thought to be triggered by aberrant translation termination at stop codons located in an environment of the mRNP that is devoid of signals necessary for proper termination. In mammals, the cytoplasmic poly(A)-binding protein 1 (PABPC1) has been reported to promote correct termination and therewith antagonize NMD by interacting with the eukaryotic release factors 1 (eRF1) and 3 (eRF3). Using tethering assays in which proteins of interest are recruited as MS2 fusions to a NMD reporter transcript, we show that the three N-terminal RNA recognition motifs (RRMs) of PABPC1 are sufficient to antagonize NMD, while the eRF3-interacting C-terminal domain is dispensable. The RRM1-3 portion of PABPC1 interacts with eukaryotic initiation factor 4G (eIF4G) and tethering of eIF4G to the NMD reporter also suppresses NMD. We identified the interactions of the eIF4G N-terminus with PABPC1 and the eIF4G core domain with eIF3 as two genetically separable features that independently enable tethered eIF4G to inhibit NMD. Collectively, our results reveal a function of PABPC1, eIF4G and eIF3 in translation termination and NMD suppression, and they provide additional evidence for a tight coupling between translation termination and initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Codon, Nonsense / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Eukaryotic Initiation Factor-4G / chemistry
  • Eukaryotic Initiation Factor-4G / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Nonsense Mediated mRNA Decay*
  • Poly(A)-Binding Protein I / chemistry
  • Poly(A)-Binding Protein I / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Subunits
  • Proto-Oncogene Proteins c-ets / chemistry
  • Proto-Oncogene Proteins c-ets / metabolism
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism


  • Codon, Nonsense
  • DNA-Binding Proteins
  • ELF3 protein, human
  • Eukaryotic Initiation Factor-4G
  • Poly(A)-Binding Protein I
  • Protein Subunits
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Tumor Suppressor Proteins
  • ribonucleotide reductase M2
  • RRM1 protein, human
  • Ribonucleoside Diphosphate Reductase

Grants and funding

This work was supported by grants to OM from the European Research Council (; StG 207419), the Swiss National Science Foundation (; grants 31003A-127614 and 31003A-143717), and the canton of Bern ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.