Human 4E-T represses translation of bound mRNAs and enhances microRNA-mediated silencing

Kamenska, Anastasiia; Lu, Wei-Ting; Kubacka, Dorota; Broomhead, Helen; Minshall, Nicola; Bushell, Martin; Standart, Nancy

doi:10.1093/nar/gkt1265

Cited by 77 publications

(128 citation statements)

References 65 publications

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“…Xp54 and 4E-T are both known and conserved translational repressors. The former is an ATP-dependent RNA helicase and part of the decapping machinery (Coller et al 2001;Fischer and Weis 2002;Minshall and Standart 2004), while the latter is an eIF4E-binding protein that is known to repress translation via two distinct mechanisms (Kamenska et al 2014). …”

Section: −5mentioning

confidence: 99%

“…Xp54 interacts with the protein 4E-T (Minshall et al 2007), which represses translation through two distinct mechanisms that can be differentiated by mutational analysis (Kamenska et al 2014). Expression of wild-type 4E-T represses translation of cellular mRNAs (Kamenska et al 2014).…”

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

“…Expression of wild-type 4E-T represses translation of cellular mRNAs (Kamenska et al 2014). 4E-T mutations (YLL-AAA) that disrupt binding to eIF4E lack that activity (Fig.…”

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

“…5A). 4E-T mutants that possess only the amino-terminal region (aa 1-180) bind eIF4E and are general translational repressors; importantly, they do not further repress mRNA to which they are tethered via the 3 ′ UTR (Kamenska et al 2014). Thus, 4E-T can repress translation via a canonical eIF4E-dependent mechanism (Fig.…”

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

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Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Waghray

Williams

Coon

et al. 2015

RNA

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RNA-regulatory factors bound to 3 ′ UTRs control translation and stability. Repression often is associated with poly(A) removal. The deadenylase CAF1 is a core component of the CCR4-NOT complex. Our prior studies established that CAF1 represses translation independent of deadenylation. We sought the mechanism of its deadenylation-independent repression in Xenopus oocytes. Our data reveal a chain of interacting proteins that links CAF1 to CCR4-NOT and to Xp54 and 4E-T. Association of CAF1 with NOT1, the major subunit of CCR4-NOT, is required for repression by CAF1 tethered to a reporter mRNA. Affinity purification-mass spectrometry and coimmunoprecipitation revealed that at least five members of the CCR4-NOT complex were recruited by CAF1. The recruitment of these proteins required NOT1, as did the ability of tethered CAF1 to repress translation. In turn, NOT1 was needed to recruit Xp54 and 4E-T. We examined the role of 4E-T in repression using mutations that disrupted either eIF4E-dependent or -independent mechanisms. Expression of a 4E-T truncation that still bound eIF4E alleviated repression by tethered CAF1, NOT1, and Xp54. In contrast, a mutant 4E-T that failed to bind eIF4E did not. Repression of global translation was affected only by the eIF4E-dependent mechanism. Reporters bearing IRES elements revealed that repression via tethered CAF1 and Xp54 is cap-and eIF4E-independent, but requires one or more of eIF4A, eIF4B, and eIF4G. We propose that RNA-binding proteins, and perhaps miRNAs, repress translation through an analogous chain of interactions that begin with the 3 ′ UTR-bound repressor and end with the noncanonical activity of 4E-T.

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Section: −5mentioning

confidence: 99%

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

“…Expression of wild-type 4E-T represses translation of cellular mRNAs (Kamenska et al 2014). 4E-T mutations (YLL-AAA) that disrupt binding to eIF4E lack that activity (Fig.…”

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

Section: E-t Is Responsible For Repression In An Eif4e-independent Mmentioning

confidence: 99%

See 2 more Smart Citations

Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Waghray

Williams

Coon

et al. 2015

RNA

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“…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).…”

mentioning

confidence: 99%

Cap-binding protein 4EHP effects translation silencing by microRNAs

Chapat

Jafarnejad

Matta‐Camacho

et al. 2017

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

111

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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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Novel roles of the CCR4–NOT complex

Chapat

Corbo

2014

WIREs RNA

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The CCR4-NOT complex is a multi-subunit protein complex evolutionarily conserved across eukaryotes which regulates several aspects of gene expression. A fascinating model is emerging in which this complex acts as a regulation platform, controlling gene products 'from birth to death' through the coordination of different cellular machineries involved in diverse cellular functions. Recently the CCR4-NOT functions have been extended to the control of the innate immune response through the regulation of interferon signaling. Thus, a more comprehensive picture of how CCR4-NOT allows the rapid adaptation of cells to external stress, from transcription to mRNA and protein decay, is presented and discussed here. Overall, CCR4-NOT permits the efficient and rapid adaptation of cellular gene expression in response to changes in environmental conditions and stimuli.

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Human 4E-T represses translation of bound mRNAs and enhances microRNA-mediated silencing

Cited by 77 publications

References 65 publications

Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Cap-binding protein 4EHP effects translation silencing by microRNAs

Novel roles of the CCR4–NOT complex

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