2008
DOI: 10.1016/j.cell.2008.02.030
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Upf1 Phosphorylation Triggers Translational Repression during Nonsense-Mediated mRNA Decay

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 eIF… Show more

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Cited by 265 publications
(318 citation statements)
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“…In contrast, hUPF1 expression in excess of ∼10-fold endogenous levels was associated with enhanced toxicity. High-level hUPF1 overexpression and phosphorylation enhance the interaction between hUPF1 and eIF3, preventing the 60S ribosomal subunit from joining with the 40S ribosomal subunit at initiation codons and down-regulating translation on a global scale (22). Consistent with these results, neuroprotection waned and hazard increased in neurons expressing the highest amounts of hUPF1.…”
Section: Discussionsupporting
confidence: 77%
See 1 more Smart Citation
“…In contrast, hUPF1 expression in excess of ∼10-fold endogenous levels was associated with enhanced toxicity. High-level hUPF1 overexpression and phosphorylation enhance the interaction between hUPF1 and eIF3, preventing the 60S ribosomal subunit from joining with the 40S ribosomal subunit at initiation codons and down-regulating translation on a global scale (22). Consistent with these results, neuroprotection waned and hazard increased in neurons expressing the highest amounts of hUPF1.…”
Section: Discussionsupporting
confidence: 77%
“…Elevated hUPF1 levels can repress translation (22) and trigger cell death, yet we observed improved survival in neurons overexpressing hUPF1, leading us to believe that the relationship between hUPF1 levels and survival is complex. Because protein amount is directly proportional to the intensity of the fluorophore to which it is fused (20), we labeled hUPF1 with EGFP and estimated TDP43-mApple and hUPF1-EGFP levels by measuring fluorescence intensity in the RFP and GFP channels, respectively.…”
mentioning
confidence: 93%
“…1A). Each pdRLUC-Gl test plasmid was transiently introduced into human embryonic kidney (HEK)293T cells together with the MYC-UPF1 expression vector pCMV-MYC-UPF1 (14) or, as a control, pCMV-MYC (14), and the phCMV-MUP reference plasmid, which produces mRNA that encodes the mouse major urinary protein (MUP). The resulting cell lysates were analyzed before or after immunoprecipitation (IP) by using anti-MYC.…”
Section: Termination-codon Context Determines the Extent Of Upf1 Bindingmentioning
confidence: 99%
“…Although SMG8 and SMG9 tightly associate with SMG1 to suppress its kinase activity (11,13), the EJC constituents UPF2 and UPF3 or UPF3X (also called UPF3a or UPF3b, respectively) augment the SMG1-mediated phosphorylation of UPF1 (10). Hyperphosphorylated UPF1 then binds to eIF3 of a 43S preinitiation complex, positioned at the translation initiation codon of the NMD target, to suppress further translation initiation events (14) and promote mRNA decay (15)(16)(17)(18). One or a combination of SMG5, SMG6, and SMG7 recruits protein phosphatase 2A to return UPF1 to its steady-state hypophosphorylated status (19)(20)(21)(22).…”
mentioning
confidence: 99%
“…Best described is the detection of a pretermination codon (PTC) at least 50 nt upstream of the 3′ of the splice junction by the scanning ribosome. Ribosomes that are stalled at a PTC recruit up-frameshift protein 1 (Upf1) (17) to form a link with Upf2 and Upf3 of the exon junction complex (EJC). This prevents the mRNA from translating full-length proteins and singles out the faulty mRNA for transport to processing bodies and degradation (18).…”
mentioning
confidence: 99%