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LARP1 on TOP of ribosome production.

ABSTRACT: The ribosome is an essential unit of all living organisms that commands protein synthesis, ultimately fuelling cell growth (accumulation of cell mass) and cell proliferation (increase in cell number). The eukaryotic ribosome consists of 4 ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs). Despite its fundamental role in every living organism, our present understanding of how higher eukaryotes produce the various ribosome components is incomplete. Uncovering the mechanisms utilized by human cells to generate functional ribosomes will likely have far-reaching implications in human disease. Recent biochemical and structural studies revealed La-related protein 1 (LARP1) as a key new player in RP production. LARP1 is an RNA-binding protein that belongs to the LARP superfamily; it controls the translation and stability of the mRNAs that encode RPs and translation factors, which are characterized by a 5' terminal oligopyrimidine (5'TOP) motif and are thus known as TOP mRNAs. The activity of LARP1 is regulated by the mammalian target of rapamycin complex 1 (mTORC1): a eukaryotic protein kinase complex that integrates nutrient sensing with mRNA translation, particularly that of TOP mRNAs. In this review, we provide an overview of the role of LARP1 in the control of ribosome production in multicellular eukaryotes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Capping and 5' End Modifications.

SUBMITTER: Fonseca BD

PROVIDER: S-EPMC6214789 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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LARP1 binds ribosomes and TOP mRNAs in repressed complexes

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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.

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The LARP1 La-Module recognizes both ends of TOP mRNAs.

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mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.

Project description:LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5'TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1's translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation, but only in conditions of mTORC1 inhibition.

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2024-01-15 | GSE233183 | GEO

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Project description:Terminal oligopyrimidine (TOP) motifs are sequences at the 5' ends of mRNAs that link their translation to the mTOR Complex 1 (mTORC1) nutrient-sensing signaling pathway. They are commonly regarded as discrete elements that reside on ?100 mRNAs that mostly encode translation factors. However, the full spectrum of TOP sequences and their prevalence throughout the transcriptome remain unclear, primarily because of uncertainty over the mechanism that detects them. Here, we globally analyzed translation targets of La-related protein 1 (LARP1), an RNA-binding protein and mTORC1 effector that has been shown to repress TOP mRNA translation in a few specific cases. We establish that LARP1 is the primary translation regulator of mRNAs with classical TOP motifs genome-wide, and also that these motifs are extreme instances of a broader continuum of regulatory sequences. We identify the features of TOP sequences that determine their potency and quantify these as a metric that accurately predicts mTORC1/LARP1 regulation called a TOPscore. Analysis of TOPscores across the transcriptomes of 16 mammalian tissues defines a constitutive "core" set of TOP mRNAs, but also identifies tissue-specific TOP mRNAs produced via alternative transcription initiation sites. These results establish the central role of LARP1 in TOP mRNA regulation on a transcriptome scale and show how it connects mTORC1 to a tunable and dynamic program of gene expression that is tailored to specific biological contexts.

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