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Translation regulation of specific mRNAs by RPS26 C-terminal RNA-binding tail integrates energy metabolism and AMPK-mTOR signaling

ABSTRACT: Increasing evidence suggests that ribosome composition and modifications contribute to translation control. Much less is known about the regulatory roles of mRNA binding by ribosomal proteins to specific mRNA translation and ribosome specialization. Here we used CRISPR-Cas9, to mutate the RPS26 C-terminal tail (RPS26dC) predicted to bind AUG upstream nucleotides at the exit channel. RPS26 binding to positions -10 to -16 of short 5’UTR mRNAs exerts positive and negative effects on translation directed by Kozak and TISU, respectively. Consistent with that, shortening the 5′UTR from 16 to 10 nt diminished Kozak and enhanced TISU-driven translation. As TISU is resistant and Kozak is sensitive to energy stress, we examined stress responses and found that the RPS26dC mutation confers resistance to glucose starvation and mTOR inhibition. Furthermore, the basal mTOR activity is reduced while AMPK is activated in RPS26dC cells, mirroring energy-deprived WT cells. Likewise, the translatome of RPS26dC cells is correlated to glucose-starved WT cells. Our findings uncover the central roles of RPS26 C-terminal RNA binding in energy metabolism, in the translation of mRNAs bearing specific features and in the translation tolerance of TISU genes to energy stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217180 | GEO | 2023/04/12

REPOSITORIES: GEO

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Rps26 directs mRNA-specific translation by recognition of Kozak sequence elements

Project description:The “Kozak sequence”, immediately upstream of the start codon, regulates the translational efficiency of an mRNA. Nevertheless, how this sequence is recognized remains unexplored. Here, we describe a novel approach to separate two ribosome populations from the same cells and use this method, and RNA-seq, to identify the mRNAs bound to ribosomes with and without Rps26, a protein linked to the pathogenesis of Diamond Blackfan Anemia (DBA). These analyses reveal that Rps26 contributes to recognition of the Kozak sequence in well-translated mRNAs, and that Rps26-deficient ribosomes preferentially translate mRNA from select stress response pathways. Surprisingly, we demonstrate that exposure of cells to these stresses leads to the formation of Rps26-deficient ribosomes and to the translation of their targets. Thus, Rps26-deficient ribosomes play aberrant pathogenic roles in DBA as well as physiological roles in augmenting the well-characterized stress transcriptional response with a heretofore unknown translational stress response, thereby creating a feed forward loop in gene-expression.

2017-07-30 | GSE86203 | 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

nanoCAGE reveals 5’ 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 5’-terminal oligopyrimidine [5’TOP] 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 5’TOP motifs. Moreover, nanoCAGE showed that 5’ UTR features distinguish two functionally and translationally distinct subsets of mTOR-sensitive mRNAs: i) those with short 5’ 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 5’ UTRs, and require both eIF4E and eIF4A1 for their efficient translation. Selective inhibition of translation of mRNAs harboring long 5’ 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 5’ UTR mRNAs by mTOR inhibitors results in suppression of mitochondrial respiration and predominantly cytostatic effects. Therefore, 5’ 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.

2016-03-14 | GSE77033 | GEO

Saccharomyces cerevisiae

Project description:Rps26 directs mRNA-specific translation by recognition of Kozak sequence elements

| PRJNA340886 | ENA

Translational Landscape in Human Early Neural Fate Determination

Project description:Gene expression regulation in eukaryotes is a multi-level process, including transcription, mRNA translation, and protein turnover. Many studies have reported the sophisticated transcriptional regulations during neural development, but the global translational dynamics is still ambiguous. Here, we differentiated human embryonic stem cells (ESCs) into neural progenitor cells (NPCs) with high efficiency and performed ribosome sequencing and RNA sequencing on both ESCs and NPCs. Data analysis revealed that translational controls engaged in many critical pathways and contributed significantly to neural fate determination regulation. Furthermore, we showed that the sequence characteristics in the untranslated region (UTR) might regulate translation efficiency. Specifically, genes with short 5UTR and intense Kozak sequence are associated with high translation efficiency in human ESCs, while genes with long 3'UTR are related to high translation efficiency in NPCs. In addition, we identified four biasedly-used codons (GAC, GAT, AGA, and AGG) and dozens of short open reading frames during neural progenitor differentiation. Thus, our study reveals the translational landscape during early human neural differentiation and provides insights into the regulation of cell fate determination at the translational level.

2023-03-04 | GSE208082 | GEO

Preimplantation mouse embryo proteome during 8C to 16C division

Project description:Preimplantation stages of mouse embryo development involve temporal and spatial specification and segregation of three late blastocyst cell lineages; trophectoderm (TE), primitive endoderm (PrE) and epiblast (EPI). Spatial separation of the outer TE lineage from the two inner-cell-mass (ICM) lineages (PrE and EPI) starts with the 8- to 16-cell transition and concludes following transit through the 16- to 32-cell stages. This results in a nascent early blastocyst ICM derived from descendants of primary founding inner cells and a secondarily contributed population; of which subsequent relative EPI versus PrE potencies are subject to debate. We showed that generation of primary but not the secondary ICM populations is highly dependent on temporally discreet activation of the mammalian target of rapamycin (mTOR – specifically mTORC1) around 8-cell stage M-phase entry. Moreover, that this role is mediated via the regulated function of the 7-methylguanosine- (7mG) cap binding initiation complex (EIF4F) and potentiating the translation of a subset of key but otherwise intransigent mRNAs containing 5’ UTR terminal oligopyrimidine (TOP-) sequence motifs. To find out translation of which mRNAs is regulated by mTOR during 8- to 16-cell transition, we analysed proteomes of control and mTOR-inhibited embryos during this time window.

2023-08-18 | PXD039423 | Pride

Assessment of mTOR-Dependent Translational Regulation of Interferon Stimulated Genes

Project description:Type-I interferon (IFN)-induced activation of the mammalian target of rapamycin (mTOR) signaling pathway has been implicated in translational control of mRNAs encoding interferon-stimulated genes (ISGs). However, mTOR-sensitive translatomes commonly include mRNAs with a 5’ terminal oligopyrimidine tract (TOP), such as those encoding ribosomal proteins, but not ISGs. Because these translatomes were obtained under conditions when ISG expression is not induced, we examined the mTOR-sensitive translatome in human WISH cells stimulated with IFNβ. The mTOR inhibitor Torin1 resulted in a repression of global protein synthesis, including that of ISG products, and translation of all but 3 ISG mRNAs (TLR3, NT5C3A, and RNF19B) was not selectively more sensitive to mTOR inhibition. Detailed studies of NT5C3A revealed an IFN-induced change in transcription start site resulting in a switch from a non-TOP to a TOP-like transcript variant and mTOR sensitive translation. Thus, we show that, in the cell model used, translation of the vast majority of ISG mRNAs is not selectively sensitive to mTOR activity and describe an uncharacterized mechanism wherein the 5’-UTR of an mRNA is altered in response to a cytokine, resulting in a shift from mTOR-insensitive to mTOR-sensitive translation.

2015-07-07 | GSE70270 | GEO

Rapamycin-Induced Feedback Activation of mRNA Translation in Pancreatic Cancer

Project description:We report mTOR inhibitor Rapamycin's specific and genome-wide effect on mRNA translation. Using ribosome footprinting in pancreatic cancer cells that lack 4EBP1 expression we establish the effect of mTOR-S6-dependent mRNA translation, and identify translation programs activated following mTOR inhibition.

2023-02-21 | GSE225683 | GEO

Ribosome profiling study of rli1 depeletion strain

Project description:ABCE1/Rli1 functions as a ribosome recycling factor in vitro, but has not been shown to be crucial for recycling in vivo. We use ribosome profiling and biochemistry to define the role of Rli1 in living yeast. When Rli1 levels were diminished, 80S ribosomes accumulated at stop codons and, surprisingly, in the adjoining 3'UTRs of most genes. While ribosomes did not show preference for any reading frame in the 3'UTR, their enrichment at stop codons and His codons after histidine starvation is consistent with aberrant 3'UTR translation. Predicted 3'UTR translation products were detected by Western analysis and mass spectrometry, and their small sizes indicate a reinitiation mechanism. Eliminating ribosome-rescue factor Dom34 dramatically increases 3'UTR ribosome occupancy in Rli1 depleted cells, indicating that Dom34 clears the bulk of unrecycled ribosomes. Thus, Rli1 is crucial for ribosome recycling in vivo and for overall gene expression as it controls ribosome homeostasis and 3'UTR translation.

2015-06-02 | GSE69414 | GEO

eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [Ribo-Seq and Ti-Seq]

Project description:The Ribo-seq and TI-seq analysis following i14G1s (eI1-eIF4G1 inhibitors) treatments uncover opposing roles of eIF1-eIF4G1 and eIF4E-eIF4G1 in scanning-dependent and independent translation. Furthermore, i14G1s inhibition of eIF4G1-eIF1 resulted in translation activation of ER/UPR stress-response genes via enhanced ribosome loading, elevated 5’UTR translation at near cognate AUGs, and unexpected concomitant upregulation of coding-region translation.

2022-07-07 | GSE166742 | GEO

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