EIF4E-independent translation is largely eIF3d-dependent
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ABSTRACT:
PROVIDER: PRJNA1019669 | ENA |
REPOSITORIES: ENA
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Project description:We study here how mRNAs are translated in an eIF4E1-independent manner by blocking eIF4E1 using a constitutively active version of eIF4E-binding protein (4E-BP). Via ribosome profiling we identify a subset of mRNAs that are still efficiently translated when eIF4E1 is inactive. We find that these mRNAs preferentially release eIF4E1 when eIF4E1 is inactive and bind instead to eIF3D via its cap-binding pocket. eIF3D then enables these mRNAs to be efficiently translated due to its cap-binding activity.
2024-08-07 | GSE243708 | GEO
Project description:eIF4E/mTOR-independent mRNA translation plasticity conferred by DAP5/eIF3d is required for breast cancer cell mesenchymal transition and metastasis
| PRJNA780006 | ENA
Project description:Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by induction of distinct gene programs tailored to each stress condition. Although the mechanisms that lead to general repression of protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here we show that the noncanonical 5′ cap-binding protein eIF3d is specifically activated in response to metabolic stress, due to loss of CK2-mediated phosphorylation near the eIF3d cap-binding pocket. Activated eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mTOR pathway, and eIF3d-mediated translation adaptation is essential for cell survival during chronic glucose deprivation. Our findings reveal a new mechanism of translation reprogramming engaged in response to metabolic stress.
2020-11-16 | GSE158249 | GEO
Project description:Translation initiation is a rate-limiting step in protein synthesis. The eukaryotic translation initiation factor 4E (eIF4E) plays an essential role in the translation initiation process. However, how eIF4E-dependent translation initiation regulates plant growth and development remains not fully understood. In this study, we have found that Arabidopsis eIF4E proteins distribute both in the nucleus and cytoplasm, and only cytoplasmic eIF4E is implicated in the control of flowering time. Results of profiling the genome-wide translation by Ribo-tag sequencing further reveal that eIF4E may regulate plant flowering by affecting homeostatic translation of flowering-time genes, including the Central Oscillator Genes (COGs). Consistent with the hypothesis that transcription-translation feedback loop is the core mechanism to drive the oscillation of circadian clock, we show that the eIF4E-dependent translation modulates the rhythmic oscillation of protein abundance of the clock-related genes (CCGs). Together, our study provides mechanistic insights into how the protein translation regulates multiple developmental processed in Arabidopsis including circadian clock and photoperiodic flowering.
2023-10-25 | GSE245858 | GEO
Project description:All cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating select gene programs necessary for survival. Here, we show the fundamental integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d which acts as a master effector to control core stress response orchestrators, the translation factor eIF2ɑ and the transcription factor ATF4. We find that during persistent stress, eIF3d activates translation of the protein kinase GCN2, inducing eIF2ɑ phosphorylation and inhibiting global protein synthesis. In parallel, eIF3d upregulates the m6A demethylase enzyme ALKBH5 to drive 5′ UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames. Our results reveal that eIF3d acts as a critical life-or-death decision point during adaptation to chronic stress and uncover a synergistic signaling mechanism in which translational cascades dynamically complement transcriptional amplification to control essential cellular processes.
2023-09-11 | GSE236188 | GEO
Project description:Caf20p is one of two Saccharomyces cerevisiae eIF4E binding proteins (4E-BPs) involved in translational control. Both 4E-BPs inhibit translation of a different subset of mRNAs, indicating that 4E-BPs bind specific targets. We used normal and mutated Caf20p to perform RIP-Seq analyses in order to explore the ability of Caf20p for binding mRNAs in 4E-dependent and 4E-independent manners.
2015-09-30 | E-MTAB-2892 | biostudies-arrayexpress
Project description:Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phos-phorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investi-gated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis. The most highly phosphorylated mitotic 4E-BP1 isoform (δ) did not interact with eIF4E, whereas a distinct 4E-BP1 phospho-isoform, EB-γ—phosphorylated at Thr-70, Ser-83, and Ser-101—bound to eIF4E during mitosis. Two-dimensional gel electropho-retic analysis corroborated the identity of the phosphorylation marks on the eIF4E-bound 4E-BP1 isoforms and uncovered a population of phosphorylated 4E-BP1 molecules lacking Thr-37/Thr-46–priming phosphorylation. Moreover, proximity ligation assays for phospho–4E-BP1 and eIF4E revealed different in situ interactions during interphase and mitosis. The eIF4E:eIF4G interaction was not inhibited, but rather increased in mitotic cells, consistent with active translation initiation during mitosis. Phospho-defective substitution of 4E-BP1 at Ser-83 did not change global translation or individual mRNA translation profiles as measured by single-cell nascent protein synthesis and eIF4G RNA-immunoprecipitation sequencing. Mitotic 5’-terminal oligopyrimidine RNA translation was active and, unlike interphase translation, resistant to mTOR inhibition. Our findings reveal the phosphorylation profiles of 4E-BP1 isoforms and their interactions with eIF4E throughout the cell cycle and indicate that 4E-BP1 does not specifically inhibit translation initiation during mitosis.
2019-06-14 | GSE131668 | GEO
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
Project description:Combining a genetic and pharmacological approach, we modulated eIF4E activity across its physiological activity range and identified subsets of genes whose translation was either hypo- or hyper- sensitive to eIF4E activity changes. eIF4E hypersensitive genes had longer 5'UTRs with higher GC content; and longer 3'UTRs with lower GC content and a higher density of unique microRNA target sites. Proliferation related genes were enriched among eIF4E hypersensitive genes; and consistent with this, decreasing eIF4E activity inhibited cell cycle transit. Our findings provide genome wide insights into the properties of mRNAs under translational control across the physiological range of eIF4E activity.
2015-12-31 | GSE56072 | GEO
Project description:Combining a genetic and pharmacological approach, we modulated eIF4E activity across its physiological activity range and identified subsets of genes whose translation was either hypo- or hyper- sensitive to eIF4E activity changes. eIF4E hypersensitive genes had longer 5'UTRs with higher GC content; and longer 3'UTRs with lower GC content and a higher density of unique microRNA target sites. Proliferation related genes were enriched among eIF4E hypersensitive genes; and consistent with this, decreasing eIF4E activity inhibited cell cycle transit. Our findings provide genome wide insights into the properties of mRNAs under translational control across the physiological range of eIF4E activity. NIH 3T3 derivatives genetically altered to induce eIF4E when treated with mifepristone and a non-inducible control NIH 3T3 derivative were cultured with or without treatment with mifepristone and varying doses of a pharmacological eIF4E inhibiting agent, 4Ei-1 (0 μM, 10 μM, 50 μM, 100 μM, 200 μM). Total RNA and polyribosome RNA were isolated after 4h of treatment. Three replicates of each experimental group were completed. In addition, three replicates of the inducible cell line treated with less potent analog to the inhibiting agent, 4Ei-4, were completed to probe for non-specific drug effects.
2015-12-31 | E-GEOD-56072 | biostudies-arrayexpress