Controlling ribosome biogenesis by mTORC1-mediated phosphorylation of LARP1
Bibliographic record
Abstract
In human cells, the control of ribosome biogenesis is in part owed to a 5’ terminal oligo-pyrimidine tract (TOP), which is harbored by mRNAs encoding e.g. ribosomal proteins. The TOP-motif enables La-Related Protein 1 (LARP1) to specifically stabilize TOP mRNAs. In addition, conditions such as shortage of nutrition or abrogated growth signaling, inactivate Mammalian Target Of Rapamycin Complex 1 (mTORC1), thereby inducing a prominent LARP1-mediated translational repression of TOP mRNAs. TOP mRNA translation is suggestively overseen by several TOP-specific regulators. Moreover, the mTORC1-targeted sites in LARP1 and the mechanism and diversity of LARP1-mediated stabilization of transcripts remain poorly characterized. Therefore, this thesis aims to reevaluate TOP-specific regulators, while focusing on how mTORC1 controls LARP1. Additionally, the present study investigates a decay-related mechanism that targets TOP mRNAs, and it also assesses the diversity and biological relevance of LARP1-mediated control of non-TOP mRNA expression. I emphasize that, among known regulators, LARP1 is the most prominent TOP-specific translational regulator, although other uncharacterized mechanisms likely complement LARP1. To efficiently control LARP1, mTORC1 may depend on interacting with an interface on LARP1 that comprises residues S550, S554, S689, T692 and S697. I verify that 26 serines and threonine residues in LARP1 are likely targeted for phosphorylation by mTORC1. Among these, the phosphorylation of LARP1 at S747, T768, S770, S772, S774, S776, T779, S784, T788, and S791 results in the release of LARP1 from the TOP-motif and rescues TOP mRNA translation, thus strongly suggesting that mTORC1 targets these sites to control LARP1-mediated translational repression of TOP mRNAs. Such detailed characterization of mTORC1-mediated control of LARP1 is unprecedented. I verify that select TOP mRNAs likely experience an endoribonucleolytic cleavage immediately downstream of the TOP-motif, thereby committing the cleaved transcripts to decay. These TOP mRNAs are targeted by an yet unknown endoribonuclease in a co-translational manner that also depends on the TOP-motif. Moreover, the presented data suggests that LARP1 is capable of stabilizing TOP mRNAs by inhibiting the endoribonucleolytic event, at least during mTORC1 inactivation. This thesis presents the first identification of TOP mRNA decay intermediates, which arise in a LARP1-regulated TOP-dependent manner. Finally, I verify that numerous non-TOP transcripts experience a LARP1-dependent post-transcriptional regulation of their abundance and translation, during proliferative conditions and mTORC1 inactivation. I emphasize that select LARP1-regulated candidates should be investigated in future studies, due to their relation to ribosome biogenesis (NPM1), mTORC1 signaling (YWHAE, MID1, Rheb, NDRG1) and resource homeostasis (PKM, MTR, QARS). In parallel, this bioinformatical study also assesses TOP mRNAs, thereby providing the first individual analysis of LARP1-dependent changes in both transcript abundance and translation for TOP and non-TOP mRNAs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".