The eukaryotic mRNA decapping protein Dcp1 interacts physically and functionally with the eIF4F translation initiation complex

Vilela, Cristina

doi:10.1093/emboj/19.16.4372

Cited by 81 publications

(63 citation statements)

References 47 publications

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“…Recent studies on the eIF4G-associated decapping enzyme Dcp1 in Saccharomyces cerevisiae have shown that eIF4E protects mRNA against degradation (27,28). One could speculate that phosphorylation of eIF4E would not only enhance initiation but also increase the susceptibility of the mRNA to decapping and subsequent degradation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA

Scheper¹,

Kollenburg²,

Hu³

et al. 2002

Journal of Biological Chemistry

230

198

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In eukaryotes, a key step in the initiation of translation is the binding of the eukaryotic initiation factor 4E (eIF4E) to the cap structure of the mRNA. Subsequent recruitment of several components, including the small ribosomal subunit, is thought to allow migration of initiation complexes and recognition of the initiation codon. Mitogens and cytokines stimulate the phosphorylation of eIF4E at Ser 209 , but the functional consequences of this modification have remained a major unresolved question. Using fluorescence spectroscopy and surface plasmon resonance techniques, we show that phosphorylation of eIF4E markedly reduces its affinity for capped RNA, primarily due to an increased rate of dissociation. Variant eIF4E proteins harboring negatively charged acidic residues at position 209 also showed decreased binding to capped RNA. Furthermore, a basic residue at position 159 was shown to be essential for cap binding. Although eIF4E-binding protein 1 greatly stabilized binding of phosphorylated eIF4E to capped RNA, in the presence of eIF4E-binding protein 1 the phosphorylated form still dissociated faster compared with nonphopshorylated eIF4E. The implications of our findings for the mechanism of translation initiation are discussed.In eukaryotic cells, all nucleus-encoded mRNAs possess a so-called "cap structure" at their 5Ј-end. This cap consists of a methylated 5Ј-5Ј bound guanosine triphosphate (m 7 GTP) moiety. The cap plays a key role in the translation of the mRNA by permitting recruitment of the eukaryotic initiation factors (eIFs) 1 required for the attachment of the ribosome and correct initiation of translation. The protein that interacts directly with the cap is eIF4E, which forms a complex with the scaffolding protein eIF4G, which in turn recruits other factors. These include eIF4A and eIF4B, which are involved in unwinding secondary structure in the 5Ј-untranslated region of the mRNA, and the poly(A)-binding protein, which by interacting with the 3Ј-tail of the mRNA circularizes it (1, 2). eIF4E also binds to small regulatory proteins termed eIF4E-binding proteins (4E-BPs). These compete with eIF4G for binding to overlapping sites on eIF4E and thus inhibit formation of initiation complexes (3, 4).It has long been known that eIF4E undergoes regulated phosphorylation, and the site has been identified as Ser 209 (5, 6). Phosphorylation of eIF4E is increased by mitogenic stimuli that activate translation (reviewed in Ref. 7) and by cytokines (8, 9). Recently, two kinases were identified that phosphorylate Ser 209 in eIF4E and are targets for the mitogen-activated extracellular signal-regulated kinase and stress/cytokine-activated p38 mitogen-activated protein kinase pathways (9 -13). These enzymes (Mnk1 and Mnk2) also associate with eIF4G in vivo (11,12,14). Despite these advances and the large number of studies on the changes of eIF4E phosphorylation in vivo, the key issue of the effect of phosphorylation on the function of eIF4E has received little attention and has remained a major question in the ...

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA

Scheper¹,

Kollenburg²,

Hu³

et al. 2002

Journal of Biological Chemistry

230

198

View full text Add to dashboard Cite

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“…In S. cerevisiae, the enzyme Dcp1 is a key protein in the decapping process during mRNA degradation (for a review on mRNA degradation see Tucker and Parker, 2000) and has recently been reported to interact with eIF4G (Vilela et al, 2000). This association occurs within the N-terminal domain of eIF4G but is very weak and by no means can compete with the eIF4E or PABP binding sites.…”

Section: Other Cellular Interacting Partnersmentioning

confidence: 99%

Conducting the initiation of protein synthesis: the role of eIF4G

Prévot

Darlix

Ohlmann

2003

Biology of the Cell

200

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The eukaryotic initiation factor eIF4G is a large modular protein which serves as a docking site for initiation factors and proteins involved in RNA translation. Together with eIF4E and eIF4A, eIF4G constitutes the eIF4F complex which is a key component in promoting ribosome binding to the mRNA. Thus, the central role of eIF4G in initiation makes it a valid target for events aimed at modulating translation. Such events occur during viral infection by picornaviruses and lentiviruses and result in the hijack of the translational machinery through cleavage of eIF4G. Proteolysis of eIF4G is also mediated by caspases during the onset of apoptosis causing inhibition of protein synthesis. We will review the role of eIF4G and protein partners as well as the cellular and viral events that modulate eIF4G activity in the initiation of translation.

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“…We previously reported that human Y14 interacts with the decapping complex and inhibits the activity of Dcp2 (22). The eukaryotic translation initiation factor 4E (eIF4E) competes with Dcp1 for binding to the cap structure and inhibits the decapping activity of Dcp2, whereby it prevents mRNA decay (19). Moreover, the cytoplasmic poly(A)-binding protein also inhibits Dcp2, suggesting that translation competes with mRNA decay (18).…”

mentioning

confidence: 99%

A Point Mutation in the Exon Junction Complex Factor Y14 Disrupts Its Function in mRNA Cap Binding and Translation Enhancement

Chuang

Lee

Lou

et al. 2016

Journal of Biological Chemistry

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Eukaryotic mRNA biogenesis involves a series of interconnected steps mediated by RNA-binding proteins. The exon junction complex core protein Y14 is required for nonsense-mediated mRNA decay (NMD) and promotes translation. Moreover, Y14 binds the cap structure of mRNAs and inhibits the activity of the decapping enzyme Dcp2. In this report, we show that an evolutionarily conserved tryptophan residue (Trp-73) of Y14 is critical for its binding to the mRNA cap structure. A Trp-73 mutant (W73V) bound weakly to mRNAs and failed to protect them from degradation. However, this mutant could still interact with the NMD and mRNA degradation factors and retained partial NMD activity. In addition, we found that the W73V mutant could not interact with translation initiation factors. Overexpression of W73V suppressed reporter mRNA translation in vitro and in vivo and reduced the level of a set of nascent proteins. These results reveal a residue of Y14 that confers capbinding activity and is essential for Y14-mediated enhancement of translation. Finally, we demonstrated that Y14 may selectively and differentially modulate protein biosynthesis.The post-splicing processing factor Y14 is involved in multiple steps of mRNA biogenesis (1-5). Y14 forms a heterodimer with Mago (6, 7). Y14/Mago genes have coevolved in a wide range of species except for yeast and are essential for germ cell determination during gametogenesis (8). Drosophila Y14/ Mago participates in the transport and translational control of posterior mRNAs during oogenesis (6, 9, 10). In vertebrates, Y14/Mago acts as a core component of the exon junction complex (EJC), 2 which is deposited immediately upstream of every ligated exon during precursor mRNA (pre-mRNA) splicing, and is thus involved in mRNA export, nonsense-mediated mRNA decay (NMD), and translation control (3,5,7,11).Y14 is present in ribosome-associated mRNA ribonucleoprotein (mRNP) fractions (12), and depletion of Y14 inhibits splicing-dependent translational activation (5). In general, the EJC factors act in concert to promote the pioneer round of translation. The Y14/Magoh interacting partner PYM interacts with ribosomal proteins and thus enhances the translation of EJC-bound spliced mRNAs (13). This observation further underscores the importance of Y14 in EJC-mediated translational control. When tethered to a reporter mRNA, Y14 enhances translation, as has been observed with other EJC and NMD factors (11). Y14 may function early during translation, whereas another EJC core factor, eIF4AIII, activates translation after 80S ribosome complex formation (5). Hence, perhaps individual EJC factors modulate productive translation via different mechanisms and in a gene-specific manner.Eukaryotic mRNA decay involves deadenylation-triggered decapping followed by 5Ј to 3Ј exonucleolytic degradation (14,15). Decapping is catalyzed by Dcp2 and is positively and negatively regulated by decapping activators and translation factors, respectively (16 -21). We previously reported that human Y14 interacts with the decap...

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The eukaryotic mRNA decapping protein Dcp1 interacts physically and functionally with the eIF4F translation initiation complex

Cited by 81 publications

References 47 publications

Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA

Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA

Conducting the initiation of protein synthesis: the role of eIF4G

A Point Mutation in the Exon Junction Complex Factor Y14 Disrupts Its Function in mRNA Cap Binding and Translation Enhancement

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