Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay

Cell. 2008 Apr 18;133(2):314-27. doi: 10.1016/j.cell.2008.02.030.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense
  • HeLa Cells
  • Hepacivirus / metabolism
  • Humans
  • Phosphorylation
  • Protein Biosynthesis*
  • RNA Helicases
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • Ribonucleoproteins / metabolism
  • Trans-Activators / metabolism*


  • Codon, Nonsense
  • RNA, Messenger
  • Ribonucleoproteins
  • Trans-Activators
  • messenger ribonucleoprotein
  • RNA Helicases
  • UPF1 protein, human