A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development

Morita, Masahiro; Ler, Lian Wee; Fabian, Marc R.; Siddiqui, Nadeem; Mullin, Michael; Henderson, Valerie C.; Alain, Tommy; Fonseca, Bruno D.; Karashchuk, Galina; Bennett, Christopher F.; Kabuta, Tomohiro; Higashi, Shinji; Larsson, Ola; Topisirović, Ivan; Smith, Robert J.; Gingras, Anne‐Claude; Sonenberg, Nahum

doi:10.1128/mcb.00455-12

Cited by 171 publications

(272 citation statements)

References 47 publications

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“…1A and Dataset S1]. The list of proteins identified for 4EHP is consistent with previous reports showing that 4EHP interacts with GIGYF1, GIGYF2, ZNF598, and 4E-T proteins (26). Known interactions with eIF4E, such as 4E-BP1 (EIF4EBP1), eIF4G1, and eIF4G3, were also detected (31).…”

Section: Resultssupporting

confidence: 74%

“…A similar mechanism functions in the mouse, where 4EHP binds the Prep1 RNA-binding protein and inhibits Hoxb4 mRNA translation (25). Moreover, 4EHP forms a translational repressor complex with GIGYF2 (Grb10-interacting GYF protein 2), which acts as a cofactor in translational repression and mRNA decay of tristetraprolin-targeted mRNAs (26,27).In this work, we demonstrate that 4EHP interacts with the mRNA-silencing machinery and engenders miRNA-mediated translational repression. Our data support a model wherein 4EHP interactions with miRISC/CCR4-NOT lead to the translational repression of miRNA targets.…”

mentioning

confidence: 76%

“…Reporter constructs were transfected into mouse embryonic fibroblasts (MEFs) from WT or 4EHP-knockout (KO) mice ( Fig. S2A) (26). The reporter containing the WT 3′ UTR of Hmga2 was repressed 4.4-fold in WT MEFs compared with the mutated, control reporter ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The specificity of eIF4E and 4EHP for their mRNA targets and their affinities for the cap are influenced by binding partners (2,26,28). Thus, we used the BioID assay (29) to identify the eIF4E and 4EHP interacting proteins.…”

Section: Resultsmentioning

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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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: Resultssupporting

confidence: 74%

mentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

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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Molecular Highway Patrol for Ribosome Collisions

et al. 2023

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During translation, messenger RNAs (mRNAs) are decoded by ribosomes which can stall for various reasons. These include chemical damage, codon composition, starvation, or translation inhibition. Trailing ribosomes can collide with stalled ribosomes, potentially leading to dysfunctional or toxic proteins. Such aberrant proteins can form aggregates and favor diseases, especially neurodegeneration. To prevent this, both eukaryotes and bacteria have evolved different pathways to remove faulty nascent peptides, mRNAs and defective ribosomes from the collided complex. In eukaryotes, ubiquitin ligases play central roles in triggering downstream responses and several complexes have been characterized that split affected ribosomes and facilitate degradation of the various components. As collided ribosomes signal translation stress to affected cells, in eukaryotes additional stress response pathways are triggered when collisions are sensed. These pathways inhibit translation and modulate cell survival and immune responses. Here, we summarize the current state of knowledge about rescue and stress response pathways triggered by ribosome collisions.

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Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

Chen

Chang

Huang

2018

Developmental Neurobiology

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Regulated local translation—whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals—allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system’s development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism‐risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof‐of‐principle regimens for use in autism mouse models to correct dysregulated translation.

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A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development

Cited by 171 publications

References 47 publications

Cap-binding protein 4EHP effects translation silencing by microRNAs

Cap-binding protein 4EHP effects translation silencing by microRNAs

Molecular Highway Patrol for Ribosome Collisions

Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

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