EIF4A1 is essential in B cells by promoting activation-induced translation
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ABSTRACT:
PROVIDER: PRJNA994938 | ENA |
REPOSITORIES: ENA
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Project description:EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5’ untranslated regions but very little is known of their roles in non-malignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. Following activation, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable whereas Hippuristanol treatment induces cell death.
2023-07-21 | GSE237426 | GEO
Project description:EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5’ untranslated regions. However, very little is known of their roles in non-malignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. Following B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.
2023-11-09 | PXD046710 | Pride
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
Project description:Eukaryotic translation initiation factor (eIF) 4A — a DEAD-box RNA-binding protein — plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here, we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs (TOP mRNAs), whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the affinity between TOP mRNAs and LARP1 and thus ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.
2024-02-13 | GSE184247 | GEO
Project description:Hippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitmentt o mRNA templates. Using a CRISPR/Cas9-based variomics screen, we identify functional eIF4A1 Hipp-resistant alleles, which in turn allow us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target-engagement. Genome-wide translational profiling in the absence or presence of Hipp (~EC50) were undertaken and our validation studies provided insight into structure-activity relationships of eIF4A-dependent mRNAs.
2020-08-05 | GSE151687 | GEO
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
Project description:To identify which genes were regulated by mRNA helicase activity, the effect of eIF4A1 knockdown on the MCF7 cell transcriptome and translatome was determined. eIF4A1-dependent mRNAs were highly enriched for several classes of genes with oncogenic potential, which leads to a model whereby dysregulation of mRNA unwinding contribues to the malignant phenotype in breast cancer cells via preferential translation of a subset of genes.
2014-12-01 | GSE58080 | GEO
Project description:To identify which genes were regulated by mRNA helicase activity, the effect of eIF4A1 knockdown on the MCF7 cell transcriptome and translatome was determined. eIF4A1-dependent mRNAs were highly enriched for several classes of genes with oncogenic potential, which leads to a model whereby dysregulation of mRNA unwinding contribues to the malignant phenotype in breast cancer cells via preferential translation of a subset of genes.
2014-12-01 | GSE58111 | GEO
Project description:eIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation
| PRJNA1001020 | ENA
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