The eIF4E-Binding Protein 4E-T Is a Component of the mRNA Decay Machinery that Bridges the 5′ and 3′ Termini of Target mRNAs

Nishimura, Tamiko; Padamsi, Zoya; Fakim, Hana; Milette, Simon; Dunham, Wade H.; Gingras, Anne‐Claude; Fabian, Marc R.

doi:10.1016/j.celrep.2015.04.065

Cited by 72 publications

(104 citation statements)

References 44 publications

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“…It was recently reported that 4E-T is recruited to mRNAs targeted by CCR4-NOT and that 4E-T functions as an important cofactor of the mRNA decay machinery (13). This finding raises the intriguing possibility that 4E-T may play a dual role in miRNA-mediated silencing: interaction of 4E-T with 4EHP potentiates translation repression, whereas its direct binding to eIF4E enables mRNA decay.…”

Section: Discussionmentioning

confidence: 99%

“…The silencing activity of miRISC is mediated by the CCR4-NOT deadenylase complex through the scaffolding subunit, CNOT1 (6)(7)(8). CNOT1 recruits the DDX6 and 4E-T (eIF4E transporter, also known as EIF4ENIF1) proteins, which are important for miRNA-mediated silencing (9)(10)(11)(12)(13)(14)(15)(16). The 4E-T protein is a conserved eIF4E-binding protein, which directly binds to the dorsal surface of eIF4E through its canonical eIF4E-binding YX 4 LL (Y 30 TKEELL) motif and impairs the eIF4E/eIF4G interaction and translation initiation (17).…”

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confidence: 99%

“…The 4E-T protein is a conserved eIF4E-binding protein, which directly binds to the dorsal surface of eIF4E through its canonical eIF4E-binding YX 4 LL (Y 30 TKEELL) motif and impairs the eIF4E/eIF4G interaction and translation initiation (17). The 4E-T protein also facilitates the decay of CCR4-NOT-targeted mRNAs by linking the 3′-terminal mRNA decay machinery to the cap via its interaction with eIF4E (13).…”

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Cap-binding protein 4EHP effects translation silencing by microRNAs

Chapat

Jafarnejad

Matta‐Camacho

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4-NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4-NOT complex. Our results show that 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases the affinity of 4EHP for the cap. We propose a model wherein the 4E-T/4EHP interaction engenders a closed-loop mRNA conformation that blocks translational initiation of miRNA targets.M icroRNAs (miRNAs) are short, ∼22-nucleotide noncoding RNAs that affect gene expression in most eukaryotes. miRNAs mediate posttranscriptional silencing by guiding the miRNA-induced silencing complex (miRISC), an assembly of Argonautes and GW182/TNRC6 proteins, to target mRNAs. Target recognition initiates a succession of events: mRNA translational repression, deadenylation, and mRNA decay (1). miRNAs impair the function of eIF4F, a three-subunit complex composed of eIF4E, the m 7 GTP (cap)-interacting factor; eIF4G, a scaffolding protein; and eIF4A, a DEAD-box RNA helicase (2-5). The silencing activity of miRISC is mediated by the CCR4-NOT deadenylase complex through the scaffolding subunit, CNOT1 (6-8). CNOT1 recruits the DDX6 and 4E-T (eIF4E transporter, also known as EIF4ENIF1) proteins, which are important for miRNA-mediated silencing (9-16). The 4E-T protein is a conserved eIF4E-binding protein, which directly binds to the dorsal surface of eIF4E through its canonical eIF4E-binding YX 4 LL (Y 30 TKEELL) motif and impairs the eIF4E/eIF4G interaction and translation initiation (17). The 4E-T protein also facilitates the decay of CCR4-NOT-targeted mRNAs by linking the 3′-terminal mRNA decay machinery to the cap via its interaction with eIF4E (13).In mammals, eIF4E is the best-studied member of a family of proteins composed of eIF4E (eIF4E1), 4EHP (4E-homologous protein; eIF4E2), and eIF4E3. The 4EHP and eIF4E proteins share 28% sequence identity (18,19). The 4EHP protein is ubiquitously expressed, and it is 5-10 times less abundant than eIF4E in a number of mammalian cell lines (18)(19)(20). Like eIF4E, 4EHP binds to 4E-T, but in sharp contrast to eIF4E, it does not associate with eIF4G (18, 21). The 4EHP protein has a 30-to 100-fold weaker affinity for the cap than eIF4E due to a twoamino acid substitution in its cap-binding pocket (22).The 4EHP protein has primarily been documented as a translation repressor. In the Drosophila embryo, 4EHP associates with the RNA binding protein Bicoid to repress caudal mRNA translation (23). Similarly, 4EHP also represses the hunchback mRNA by binding to the nanos repressive element complex, which consists of nanos...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Cap-binding protein 4EHP effects translation silencing by microRNAs

Chapat

Jafarnejad

Matta‐Camacho

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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111

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“…Furthermore, we found that DDX6‐mediated repression does not require ribosomal scanning, suggesting that DDX6 may interfere with eIF4E or eIF4G function. In this context, it has been shown that DDX6 interacts with the eIF4E‐transporter protein (4E‐T; Nishimura et al , 2015; Ozgur et al , 2015), an eIF4E‐binding protein that competes with eIF4G for binding to eIF4E and represses translation initiation. However, depletion of 4E‐T only partially alleviates silencing (this study; Kamenska et al , 2014; Nishimura et al , 2015), which implies that DDX6 may employ additional mechanisms to repress translation that are thus far unknown.…”

Section: Discussionmentioning

confidence: 99%

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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AbstractmiRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4–NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4–NOT complex in Drosophila melanogaster. Here, we show that miRNAs, AGOs, GW182, the CCR4–NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning‐independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.

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“…Supporting these results, structural studies showed that CNOT1 directly interacts with DDX6 through the MIF4G domain [45,46,61]. A recent study demonstrated that in humans the eIF4E-binding protein 4E-T interacts with CNOT1 and a number of decapping activators, including PATL1, LSM14, DDX6, LSM2, and DCP1 by using a combination of coimmunoprecipitation and proximal biotinylation (Bio-ID) techniques [55]. They showed that 4E-T promotes miRNA-mediated mRNA decay through the eIF4E-binding domain, suggesting that 4E-T bridges the 3 0 -terminal mRNA decay complex to the 5 0 m 7 G-cap via binding to eIF4E [55].…”

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confidence: 80%