Upf1 Phosphorylation Triggers Translational Repression during Nonsense-Mediated mRNA Decay

Olaf Isken, Yoon Ki Kim, Nao Hosoda, Greg L. Mayeur, John W.B. Hershey, Lynne E. Maquat

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

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-tRNAiMet/mRNA to translationally competent 80S/Met-tRNAiMet/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.

Original languageEnglish
Pages (from-to)314-327
Number of pages14
JournalCell
Volume133
Issue number2
DOIs
Publication statusPublished - 2008 Apr 18

Keywords

  • PROTEINS
  • RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Isken, O., Kim, Y. K., Hosoda, N., Mayeur, G. L., Hershey, J. W. B., & Maquat, L. E. (2008). Upf1 Phosphorylation Triggers Translational Repression during Nonsense-Mediated mRNA Decay. Cell, 133(2), 314-327. https://doi.org/10.1016/j.cell.2008.02.030