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Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs

ABSTRACT: Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the protein output of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here we comprehensively determined the RNA-binding preferences of the initiation factor eIF4G to assess whether this core translation initiation factor has intrinsic sequence preferences that contribute to preferential translation of specific mRNAs.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE87614 | GEO | 2017/05/29

SECONDARY ACCESSION(S): PRJNA345383

REPOSITORIES: GEO

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Translation initiation factor eIF4G1 preferentially binds yeast transcript leaders containing conserved oligo-uridine motifs.

Project description:Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the protein output of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here, we comprehensively determined the RNA-binding preferences of the eukaryotic initiation factor 4G (eIF4G) to assess whether this core translation initiation factor has intrinsic sequence preferences that may contribute to preferential translation of specific mRNAs. We identified a simple RNA sequence motif-oligo-uridine-that mediates high-affinity binding to eIF4G in vitro. Oligo(U) motifs occur naturally in the transcript leader (TL) of hundreds of yeast genes, and mRNAs with unstructured oligo(U) motifs were enriched in immunoprecipitations against eIF4G. Ribosome profiling following depletion of eIF4G in vivo showed preferentially reduced translation of mRNAs with long TLs, including those that contain oligo(U). Finally, TL oligo(U) elements are enriched in genes with regulatory roles and are conserved between yeast species, consistent with an important cellular function. Taken together, our results demonstrate RNA sequence preferences for a general initiation factor, which cells potentially exploit for translational control of specific mRNAs.

| S-EPMC5558906 | biostudies-literature

The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs

Project description:Translation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show that eukaryote-specific Asc1/RACK1 is required for efficient translation of mRNAs with short open reading frames that show greater than average translational efficiency in diverse eukaryotes. ASC1 mutants in S. cerevisiae display compromised translation of specific functional groups, including cytoplasmic and mitochondrial ribosomal proteins, and display cellular phenotypes consistent with their gene-specific translation defects. Asc1-sensitive mRNAs are preferentially associated with the translational ‘closed loop’ complex comprised of eIF4E, eIF4G and Pab1, and depletion of eIF4G mimics the translational defects of ASC1 mutants. Together our results reveal a role for Asc1/RACK1 in a length-dependent initiation mechanism optimized for efficient translation of genes with important housekeeping functions.

2016-04-24 | GSE61753 | GEO

Yeast eIF4G homogenic whole cell oxidative stress LC-MSMS

Project description:Translation initiation factor 4G (eIF4G) is an integral component of the eIF4F complex which is key to translation initiation for most eukaryotic mRNAs. Many eIF4G isoforms have been described in diverse eukaryotic organisms but we currently have a poor understanding of their functional roles and whether they regulate translation in an mRNA specific manner. The yeast Saccharomyces cerevisiae expresses two eIF4G isoforms, eIF4G1 and eIF4G2, that have previously been considered as functionally redundant with any phenotypic differences arising due to alteration in eIF4G expression levels. Using homogenic strains that express eIF4G1 or eIF4G2 as the sole eIF4G isoforms at comparable expression levels to total eIF4G, we show that eIF4G1 is specifically required to mediate the translational response to oxidative stress. We use quantitative proteomics to show that eIF4G1 promotes oxidative stress-specific proteome changes.

2023-10-24 | PXD041682 | Pride

Widespread and dynamic translational control of red blood cell development

Project description:Cell development requires tight yet dynamic control of protein production. Here, we use murine erythropoiesis as a model to study translational regulatory dynamics during mammalian cell differentiation. We uncover pervasive translational control of protein synthesis, including widespread alternative translation initiation and termination, stoichiometric synthesis, and dynamic use of upstream reading frames. We thus unravel translational regulatory programs during erythropoiesis, comprising hundreds of mRNAs with dynamic translation efficiencies and their cell type-specific regulators. A major such program involves enhanced decoding of specific mRNAs depleted in terminally differentiating/enucleating cells with decreasing transcriptional capacity. Rbm38, an erythroid-specific RNA-binding protein, promotes translation of many such genes by recruiting the translation initiation factor eIF4G. Inhibiting Rbm38 blocks red cell production, and mice lacking Rbm38 develop anemia, demonstrating an essential role for Rbm38-mediated enhanced translation of irreplaceable mRNAs. These findings reveal critical roles for dynamic translational control in supporting specialized mammalian cell formation.

2016-12-01 | GSE83823 | GEO

Saccharomyces cerevisiae S288C

Project description:Intrinsic RNA-Binding Preferences of Eukaryotic Translation Initiation Factor eIF4G Contribute to Competitive Discrimination of Different mRNAs

| PRJNA277888 | ENA

Transcriptional and translational effect of the lack of translation initiation factor eIF(iso)4E

Project description:One of the most regulated steps of translation initiation is the recruitment of an mRNA by the translation machinery. In eukaryotes, this step is mediated by the 5M-BM-4end cap-binding factor eIF4E bound to the bridge protein eIF4G and forming the eIF4F complex. In plants, different isoforms of eIF4E and eIF4G form the antigenically distinct eIF4F and eIF(iso)4F complexes proposed to mediate selective translation. Using a microarray analysis of polyribosome- and non-polyribosome-purified mRNAs from 15 day-old Arabidopsis thaliana wild type [WT] and eIF(iso)4E knockout mutant [AteIF(iso)4E-1] seedlings we found 79 transcripts shifted from polyribosomes toward non-polyribosomes, and 47 mRNAs with the opposite behavior in the mutant. The translationally decreased mRNAs were overrepresented in root-preferentially expressed genes and proteins from the endomembrane system, including several transporters such as the phosphate transporter PHOSPHATE1 (PHO1), Sucrose transporter 3 (SUC3), the ABC transporter-like with ATPase activity (MRP11) and five electron transporters, as well as signal transduction-, protein modification- and transcription-related proteins. For transcriptional analysis used total RNA of AteIF(iso)4E-1 seedlings of 15 days old to known the changes on transcripts leves by the eIF(iso)4E absence, using as control Wt seedlings. The experiments were performed in duplicate, and swap analysis were done. For translational analysis, used non-polysomal and polysomal RNA of AteIF(iso)4E-1 seedlings of 15 days old in order to known the transcripts that are modified in their translational levels by the eIF(iso)4E absence, using as control non polysomal and polysomal RNA of Wt seddlings.

2013-07-26 | E-GEOD-29386 | biostudies-arrayexpress

DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5’ leaders

Project description:Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here, we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is required for translation initiation on select transcripts. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-dependent translation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates main CDS, but not uORF, translation suggesting a role for DAP5 in translation re-initiation. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.

2022-11-07 | GSE155854 | GEO

CERES is an eIF4E-interacting protein that forms non-canonical translation initiation complexes and modulates translation during the diel cycle in plants

Project description:Translation is a fundamental step in gene expression that regulates multiple developmental and stress responses. One key step of translation is the association between eIF4E and eIF4G. This process is regulated in different eukaryotes by proteins which bind to eIF4E and block the formation of the eIF4E/eIF4G complex. Here, we report the discovery of CERES, the first functional eIF4E regulator described in plants. CERES is a modular protein that contains a LRR domain and a canonical eIF4E binding site (4E-BS), critical for CERES interaction with eIF4E in planta. CERES/eIF4E interaction excludes eIF4G from the complex. Despite this observation, CERES promotes translation in vivo interacts with eIF4A and with eIF3 in vivo and cosediments with translation initiation complexes in sucrose gradients. Moreover, ceres mutants display a sharp increase of the 80S peak and a reduction of polysome content at specific periods of the diel cycle. Super-resolution ribosome profiling demonstrates that these mutants show a change of translation efficiency of mRNAs related to light response and glucose management. Consistently, these mutants show a hypersensitive response to glucose. These data show that CERES is a “non canonical” translation initiation factor that, through the formation of alternative translation initiation complexes, modulates translation during the light cycle in plants.

2019-12-04 | GSE124290 | GEO

Effect of stress on the binding affinity of yeast eIF4F components to their target RNAs

Project description:Translation factors eIF4E and eIF4G form eIF4F, which binds to mRNAs to promote ribosome recruitment and translation initiation. We were interested in analysing the effects of stresses on eIF4F interactions with individual mRNAs. We used a RIP-seq approach to assess how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change in response to three stresses: 1) addition of hydrogen peroxide; 2) amino acids withdrawal; and, 3) glucose withdrawal. We find that acute stress leads to changes in eIF4FmRNA interactions that are shared among each factor and across the stresses imposed.

2017-10-11 | E-MTAB-5836 | biostudies-arrayexpress

A novel oncomicropeptide encoded by DSP-AS1 exhibits proneoplastic properties in lung adenocarcinoma by facilitating YTHDF1-induced translation initiation through mediation of mRNA circularization

Project description:Functional micropeptides can hide inside RNA previously annotated as non-coding, their roles in the tumorigenesis of lung cancer remain largely unknown. Here, combining Ribo-seq, mass spectrometry and bioinformatics, we characterize a 46 amino-acid length oncogenic micropeptide encoded by lncRNA DSP-AS1, that we named Desmoplakin Associated MicroPeptide (DAMP), in lung adenocarcinoma (LUAD). DAMP is aberrantly overexpressed in LUAD and confers an unfavorable prognosis, its pro-neoplastic properties with respect to augmented proliferation, survival and invasiveness were validated in vitro and in vivo. DAMP colocalizes with translation machinery and induces translational reprogramming both by elevating global protein synthesis and by selectively upregulating the translation of mRNA group encoding oncogenic factors in LUAD. Mechanistically, DAMP simultaneously binds cap-binding subunit eIF4G and YTHDF1, a m6A reader that could fuel translation initiation by recruiting eIF3 to methylated mRNA. The above interactions lead to the formation of a “closed loop” between YTHDF1 and eIF4G bridged by DAMP, which makes YTHDF1 to be spatially in proximity with translation initiation complex and successfully loading of ribosomal 40S subunit onto target mRNAs. Targeting DAMP exhibited significant anti-cancer effects in vitro and in vivo. Our findings not only unravel the oncogenic role of a previously unrecognized micropeptide through orchestrating mRNA translation but also provide a strong rationale in the design of anti-cancer therapy targeting translation machinery in LUAD.

2023-12-04 | GSE249133 | GEO

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