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Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay.

In mammalian cells, nonsense-mediated mRNA decay (NMD) generally requires that translation terminates sufficiently upstream of a post-splicing exon junction complex (EJC) during a pioneer round of translation. The subsequent binding of Upf1 to the EJC triggers Upf1 phosphorylation. We provide evidence that phospho-Upf1 functions after nonsense codon recognition during steps that involve the translation initiation factor eIF3 and mRNA decay factors. Phospho-Upf1 interacts directly with eIF3 and inhibits the eIF3-dependent conversion of 40S/Met-tRNA(i)(Met)/mRNA to translationally competent 80S/Met-tRNA(i)(Met)/mRNA initiation complexes to repress continued translation initiation. Consistent with phospho-Upf1 impairing eIF3 function, NMD fails to detectably target nonsense-containing transcripts that initiate translation independently of eIF3 from the CrPV IRES. There is growing evidence that translational repression is a key transition that precedes mRNA delivery to the degradation machinery. Our results uncover a critical step during NMD that converts a pioneer translation initiation complex to a translationally compromised mRNP.

Pubmed ID: 18423202


  • Isken O
  • Kim YK
  • Hosoda N
  • Mayeur GL
  • Hershey JW
  • Maquat LE



Publication Data

April 18, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM073732
  • Agency: NIGMS NIH HHS, Id: GM074593
  • Agency: NIGMS NIH HHS, Id: R01 GM074593

Mesh Terms

  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Codon, Nonsense
  • HeLa Cells
  • Hepacivirus
  • Humans
  • Phosphorylation
  • Protein Biosynthesis
  • RNA Stability
  • RNA, Messenger
  • Ribonucleoproteins
  • Trans-Activators