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.
The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs.
A complex between met-tRNA F and native 40S subunits in reticulocyte lysates and its disappearance during incubation with double-stranded RNA
Protein synthesis initiation factors from human HeLa cells and rabbit reticulocytes are similar: comparison of protein structure, activities, and immunochemical properties
The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs
A mutated human homologue to yeast Upf1 protein has a dominant-negative effect on the decay of nonsense-containing mRNAs in mammalian cells
SMG-2 is a phosphorylated protein required for mRNA surveillance in Caenorhabditis elegans and related to Upf1p of yeast.
A selection system for functional internal ribosome entry site (IRES) elements: analysis of the requirement for a conserved GNRA tetraloop in the encephalomyocarditis virus IRES
Recognition of yeast mRNAs as "nonsense containing" leads to both inhibition of mRNA translation and mRNA degradation: implications for the control of mRNA decapping
Naturally occurring dicistronic cricket paralysis virus RNA is regulated by two internal ribosome entry sites.
Evidence that phosphorylation of human Upfl protein varies with intracellular location and is mediated by a wortmannin-sensitive and rapamycin-sensitive PI 3-kinase-related kinase signaling pathway
The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay
Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay
Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex
Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20
Preparation and activity of synthetic unmodified mammalian tRNAi(Met) in initiation of translation in vitro
Regulation of internal ribosomal entry site-mediated translation by phosphorylation of the translation initiation factor eIF2alpha
The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling
Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.
Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans
Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities
Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7
The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex
The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells
Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise
MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function
Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression
Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay
Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay
Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation.
Inhibition of nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII.
Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g.
Comparative proteomics reveals a significant bias toward alternative protein isoforms with conserved structure and function.
N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD.
Rapid degradation of replication-dependent histone mRNAs largely occurs on mRNAs bound by nuclear cap-binding proteins 80 and 20
SMG5-PNRC2 is functionally dominant compared with SMG5-SMG7 in mammalian nonsense-mediated mRNA decay
SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs.
Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta.
The SMG5-SMG7 heterodimer directly recruits the CCR4-NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2
CBP80-promoted mRNP rearrangements during the pioneer round of translation, nonsense-mediated mRNA decay, and thereafter
The human T-lymphotropic virus type 1 tax protein inhibits nonsense-mediated mRNA decay by interacting with INT6/EIF3E and UPF1.
Translational competence of ribosomes released from a premature termination codon is modulated by NMD factors.
Drosophila Upf1 and Upf2 loss of function inhibits cell growth and causes animal death in a Upf3-independent manner
Translation initiation factors eIF3 and HCR1 control translation termination and stop codon read-through in yeast cells
Two molecular pathways (NMD and ERAD) contribute to a genetic epilepsy associated with the GABA(A) receptor GABRA1 PTC mutation, 975delC, S326fs328X.
Eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay by two genetically separable mechanisms
Identification and functional analysis of novel phosphorylation sites in the RNA surveillance protein Upf1
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