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EIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR

ABSTRACT: Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4- Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA-selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5’UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94690 | GEO | 2019/10/09

REPOSITORIES: GEO

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eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR.

Project description:Regulation of the mRNA life-cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Here we show eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar properties to chemically inhibited eIF4A1. We demonstrate that eIF4A2 exerts it repressive effect by binding purine-rich motifs which are enriched in the 5’UTR directly upstream of the AUG start codon. The data supports a model whereby purine motifs towards the 3’ end of the 5’UTR are associated with increased ribosome occupancy and possible uORF activation similar to that observed for mRNAs affected by inhibited eIF4A1.

2019-10-08 | PXD014764 | Pride

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine rich motifs in th 5'UTR

Project description:Here we show eIF4A2 is a major effector of the represive miRNA pathway functioning via the Ccr4_Not complex; through its interaction with the Ccr4-Not complex eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar properties to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5'UTR directly upstream of the AUG codon.

2019-10-10 | PXD015772 | Pride

Selective translation mechanism through two paralogs of eukaryotic initiation factor 4A

Project description:Eukaryotic initiation factor (eIF) 4A is a DEAD-box RNA-binding protein that plays a pivotal role in translation initiation. Although mammals have two eIF4A paralogs, eIF4A1 and eIF4A2, their redundancy has been long assumed because of high homology and their functional difference has been poorly understood. Here we show that eIF4A paralogs employ differential translation programs. Ribosome profiling of eIF4A1- and eIF4A2-knockout HEK293T cell lines revealed that translation efficiency changes were divergent across transcriptome and distinct group of mRNAs were regulated by each paralog. Our analysis indicates that eIF4A1 and eIF4A2 facilitate translation of specific mRNAs.

2019-10-26 | GSE126298 | GEO

Homo sapiens

Project description:eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR

| PRJNA371822 | ENA

eIF4A1 unwinding activity is RNA sequence-specifically deployed through eIF4A1-multimerisation to facilitate translation of mRNAs with local repressive RNA structure

Project description:Oncogenic translational programmes are an emerging hallmark of cancer and often driven by dysregulation of signaling pathways including KRAS and mTORC that converge on the eukaryotic translation initiation (eIF) 4F complex. Altered eIF4F activity promotes translation of oncogene mRNAs that typically contain highly structured 5’UTRs rendering their translation strongly dependent on RNA unwinding by DEAD-box helicase eIF4A1 subunit of the eIF4F complex. In addition, eIF4A1 separately functions to load mRNA into the 43S pre-initiation complex (PIC), an essential step for the translation of cellular mRNA. While eIF4A1-dependent mRNAs have been widely investigated, it is still unclear if highly structured mRNAs recruit and activate eIF4A1 unwinding specifically. Here, we uncover that unwinding by eIF4A1 is activated in an RNA sequence-dependent manner in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain specific RNA sequences, particularly enriched for polypurine-motifs, in their 5’UTR which recruit and specifically stimulate unwinding of local repressive RNA structure by eIF4A1 in an RNA sequence-dependent manner to facilitate translation. Mechanistically, we show that polypurine-rich sequences trigger the formation of RNA sequence-specific multimeric eIF4A1-complexes, assembled of catalytically distinct eIF4A1 subunits, the joint activity of which enhances RNA unwinding activity. Together with our structural data, we describe a model in which conformational changes within eIF4A1 and the RNA through the process of eIF4A1 multimerisation, lead to an optimal interaction of eIF4A1-unwinding subunits with the structured RNA region which enhances unwinding. Hence, we conclude that RNA sequences in addition to protein cofactors contribute to the regulation of cellular eIF4A1 function and promotion of translation of eIF4A1-unwinding dependent mRNAs.

2023-01-17 | PXD034343 | Pride

Identification of eIF4A1-binding RNAs in human prostate cancer cell line DU145

Project description:We screened the translational targets of eIF4A1 in DU145 cells using the Native RNA immunoprecipitation (RIP) assay with RNA-seq (RIP-seq). The eIF4A1-binding peaks and RNA fractions were normally distributed around the ATG translation start site. A total of 197 coding genes with eFI4A1-binding peaks in mRNAs, including 5' UTR, exon, and 3' UTR regions. were identified in the eIF4A1-RIP sample. The most enriched eFI4A1-binding motifs (MAGGTA, CCASCYC, and GARGA) were identified by aligning the sequences of all eFI4A1-binding RNA fractions to a reference genome.

2022-06-29 | GSE161709 | GEO

RIP-Seq of Eif4a2 in mouse embryonic stem cell

Project description:RNA-immunoprecipitation can be used to identify transcripts bound by RNA binding proteins. Here we identified transcripts bound by the translation initiation factor Eif4a2 in ESCs. We found that several pluripotency transcription factor encoding mRNAs and factors regulating ESC differentiation show binding to Eif4a2 stronger than expected by transcript abundance.

2022-02-02 | GSE153456 | GEO

nanoCAGE reveals 5â UTR features that define specific modes of translation of functionally related mTOR-sensitive mRNAs

Project description:mTOR regulates mRNA translation. Whereas ribosome-profiling suggested that mTOR exclusively stimulates translation of TOP (containing a 5â-terminal oligopyrimidine [5âTOP] motif) and TOP-like mRNAs, polysome-profiling implied that mTOR also modulates translation of non-TOP mRNAs. We show that ribosome-, but not polysome-profiling, is biased towards identification of TOP mRNAs as differentially translated while obscuring detection of changes in non-TOP mRNA translation. Transcription start site profiling by Nano-Cap Analysis of Gene Expression (nanoCAGE) revealed that many mTOR-sensitive mRNAs do not have 5âTOP motifs. Moreover, nanoCAGE showed that 5â UTR features distinguish two functionally and translationally distinct subsets of mTOR-sensitive mRNAs: i) those with short 5â UTRs enriched for mitochondrial functions such as respiration, that are translated in an eIF4E, but not eIF4A1-dependent manner and ii) mRNAs encoding proliferation- and survival-promoting proteins, that harbor long 5â UTRs, and require both eIF4E and eIF4A1 for their efficient translation. Selective inhibition of translation of mRNAs harboring long 5â UTRs via suppression of eIF4A leads to uncoupling of expression of proteins involved in respiration (e.g. ATP5O) from those protecting mitochondrial integrity (e.g. BCL-2) ultimately resulting in apoptosis. Conversely, simultaneous translational downregulation of both long and short 5â UTR mRNAs by mTOR inhibitors results in suppression of mitochondrial respiration and predominantly cytostatic effects. Therefore, 5â UTR features define differential modes of translation of functionally distinct mTOR-sensitive mRNAs, which explains discrepancies between the effects of mTOR and eIF4A inhibitors on neoplastic cells. Determination of 5'UTR lengths using nanoCAGE in MCF7 cells

2016-03-14 | E-GEOD-77033 | biostudies-arrayexpress

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [eCLIP-seq]

Project description:Stemness is a defining feature in embryonic and cancer stem cells. How stemness is regulated at the mRNA translational initiation remains undefined. We carried out an RNAi screen for key translation initiation factors that maintain the stemness in mouse embryonic stem cells (ESCs). We identified eIF4A2 and defined its mechanistic action through Rps26-depleted and -containing ribosomes in translational initiation activation of mRNAs encoding pluripotency factors and H3.3 for embryonic and extraembryonic lineage repression, respectively. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell (2C) transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Knockdown of eIF4A2 disrupts ESC proteome causing the loss of stemness in ESCs as well as in human glioblastomas where eIF4A2 is highly enriched. Collectively, our study establishes an eIF4A2-mediated translation initiation control of stemness and provides insight into cancer therapeutics targeting the translation initiation machinery.

2022-04-20 | GSE150680 | GEO

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of embryonic and cancer stemness [Ribo-seq]

2022-04-20 | GSE150676 | GEO

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