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Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs [S4U label]

ABSTRACT: To investigate the changes in mRNA stablity upon loss of LARP1, we performed SLAM-seq and half-life measurements on WT and derived LARP1 KO cells. The canonical and 5′TOP mRNA cell lines used for single-molecule imaging were treated as biological replicates for the SLAM-seq analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233186 | GEO | 2024/01/15

REPOSITORIES: GEO

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Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs [LARP1]

Project description:To investigate the changes in gene expression upon loss of LARP1, we performed RNA-seq and differential gene expression analysis on WT and derived LARP1 KO cell lines. The canonical and 5′TOP mRNA cell lines used for single-molecule imaging were treated as biological replicates for the differential gene expression analysis.

2024-01-15 | GSE233183 | GEO

GCN2 suppresses TOP mRNA translation via LARP1

Project description:La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine tract (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5’TOP motif, resulting in the displacement of the eIF4E complex from TOP mRNAs. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. GCN2 inhibits TOP mRNA translation via ATF4-dependent transcriptional induction of LARP1 mRNAs and GCN1-mediated recruitment of LARP1 to stalled ribosomes. We performed ATF4 ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-08-31 | GSE166590 | GEO

The LARP1 homolog Slr1p controls the stability and expression of proto-5’TOP mRNAs in fission yeast [RIP-seq]

Project description:Messenger RNAs (mRNAs) in higher eukaryotes that encode highly expressed proteins important for the assembly of the translational apparatus (e.g. ribosomal proteins) often harbour a pyrimidine-rich motif at the extreme 5’ end known as a 5’ terminal oligopyrimidine (5’TOP) sequence. Members of the La-related protein 1 (LARP1) family control 5’TOP expression through a conserved DM15 motif, but the mechanism is not well understood. 5’TOP motifs have not been described in many lower organisms, but fission yeast (and many other single-celled eukaryotes) harbour a LARP1 homolog that also lacks a DM15 motif. In this work, we show that the fission yeast LARP1 homolog, Slr1p, controls the translation and stability of mRNAs encoding proteins analogous to 5’TOP mRNAs in higher eukaryotes, which we thus refer to as proto-5’TOPs. Our data suggest that the LARP1 DM15 motif and the mRNA 5’TOP motif may be features that were scaffolded over a more fundamental mechanism of LARP1 family member-associated control of gene expression that is still utilized in lower systems.

2023-07-18 | GSE237526 | GEO

The LARP1 homolog Slr1p controls the stability and expression of proto-5’TOP mRNAs in fission yeast [RNA-seq]

2023-07-21 | GSE237860 | GEO

Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs [4EBP1/2]

Project description:To investigate the changes in gene expression upon loss of 4EBP1/2, we performed RNA-seq and differential gene expression analysis on WT and derived 4EBP1/2 KD cell lines. The canonical and 5′TOP mRNA cell lines used for single-molecule imaging were treated as biological replicates for the differential gene expression analysis.

2024-01-15 | GSE233182 | GEO

mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading [LARP1 KD, Torin1]

Project description:Translation of TOP mRNAs encoding protein synthesis machinery is strictly regulated by an amino acid sensing mTOR pathway. However, its regulatory mechanism remains elusive. Here, we demonstrate that TOP mRNA translation positively correlates with its poly(A) tail length under mTOR active/amino acid-rich condition, suggesting that TOP mRNAs are post-transcriptionally controlled by poly(A) tail length regulation. Consistent with this, tail length of TOP mRNAs dynamically fluctuates in response to amino acid availability. Poly(A) tail shortens under mTOR active/ amino acid-rich condition, whereas the long-tailed TOP mRNAs accumulate under mTOR inactive/amino acid-starved (AAS) condition. An RNA-binding protein LARP1 that specifically binds to TOP mRNAs is indispensable for the process. We also show that LARP1 interacts with non-canonical poly(A) polymerases, PAPD4, PAPD5 and PAPD7 and induces post-transcriptional polyadenylation of the target when tethered to the mRNA. Our findings illustrate that LARP1 contributes to the selective accumulation of TOP mRNAs with long poly(A) tail under AAS, resulting in accelerated ribosomal loading onto TOP mRNAs for the resumption of translation after AAS.

2022-09-19 | GSE137807 | GEO

mTORC1 controls a dynamic program of TOP mRNA translation via LARP1

Project description:LARP1 has been proposed to control the translation of TOP mRNAs downstrteam of mTORC1. Here we used ribosome profiling to analyze transcriptome-wide changes in translation following mTOR inhibition in wild-type HEK-293T cells and cells where LARP1 (sgLARP1) or LARP1 and its homologue LARP1B (sgLARP1/1B) have been deleted using CRISPR/Cas9.

2020-02-12 | GSE132703 | GEO

mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading [polysome fractionation]

2022-09-22 | GSE145744 | GEO

Distinct roles of LARP1 and 4EBP1/2 in regulating translation and stability of 5′TOP mRNAs

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-15 | GSE233187 | GEO

LARP1 mRNP scaffolds mTORC1 to stimulate translation initiation of an essential class of mRNAs

Project description:The RNA biding protein, LARP1, has been proposed to function downstream of mTORC1 to positively regulate the translation of 5M-bM-^@M-^YTOP mRNAs such as ribosome protein (RP) mRNAs. However, its regulatory roles in mTORC1-mediated translation remain unclear. PAR-CLIP of LARP1 revealed its direct and dynamic interactions with RP mRNAs through pyrimidine-enriched sequences in the 5M-bM-^@M-^YUTR of RP mRNAs when mTOR activity is inhibited. Importantly, this LARP1 is a direct substrate of mTORC1 and S6K1/Akt, and phosphorylated LARP1 scaffolds mTORC1 on translation-competent mRNAs to facilitate 4EBP1 and S6K1 phosphorylation. Ablation of LARP1 causes multiple defects in the processes of translation including abnormal eIF4G1 interaction with RP mRNAs and inefficient RP mRNA elongation thereby reducing ribosome biogenesis and cell proliferation. These observations illustrate that LARP1 functions both an effector and a regulator for local mTORC1 activity, and acts as a molecular switch for ribosome biogenesis by sensing growth factor/nutrient signaling. LARP1-bound RNA regions were sequenced from HEK293T cells under growing or mTOR-inactive conditions. In parallel, mRNA abundance was quantified, in biological duplicate, from HEK293T cells under the same conditions.

2014-07-31 | E-GEOD-59599 | biostudies-arrayexpress

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