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 journalArticlepeer-review

235 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
Externally publishedYes

Bibliographical note

Funding Information:
We thank Peter Sarnow for pR/CrPV/F, Sung Key Jang for pR/HCV/F, Bill Merrick for anti-eIF2, Nahum Sonenberg for anti-eIF3b and anti-eIF4AIII, Deanna Janzen and Adam Geballe for anti-eRF3, Jens Lykke-Andersen for anti-Upf1 and anti-Dcp1a, Ger Pruijn for anti-Rrp4, Tom Parsons for anti-eIF3a, Mark Nelson for anti-eIF3f, and Paul Anderson for pMT2-HA-eIF2α plasmids. We also are grateful to Richard Jackson and Graham Belsham for helpful information. This work was supported by NIH grants GM074593 to L.E.M. and GM073732 to J.W.B.H. N.H. was supported in part by a Fellowship from the Japan Society for the Promotion of Science.

Keywords

  • PROTEINS
  • RNA

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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