The 40
            <i>S</i>
            -LARP1 complex reprograms the cellular translatome upon mTOR inhibition to preserve the protein synthetic capacity

Fuentes, Pedro Juan Barrios; Pelletier, Joffrey; Martinez-Herráez, Carolina; Díez-Obrero, Virginia; Iannizzotto, Flavia; Rubio, Teresa; Garcia‐Cajide, Marta; Menoyo, Sandra; Salazar, Ramón; Tauler, Albert; Gentilella, Antonio

doi:10.1126/sciadv.abg9275

“…Previous studies have focused on the role of LARP1 in protecting 5′TOP mRNAs in mTOR inhibited cells, as LARP1 has been shown to be recruited to 5′TOP mRNAs upon mTOR inhibition ( 24 , 51 ). Our findings raise the intriguing question of how LARP1 can be specifically recruited to 5′TOP mRNAs when mTOR is active.…”

Section: Discussionmentioning

confidence: 99%

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

Hochstoeger,

Papasaikas,

Piskadlo

et al. 2024

Sci. Adv.

5

0

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A central mechanism of mTOR complex 1 (mTORC1) signaling is the coordinated translation of ribosomal protein and translation factor mRNAs mediated by the 5′-terminal oligopyrimidine motif (5′TOP). Recently, La-related protein 1 (LARP1) was proposed to be the specific regulator of 5′TOP mRNA translation downstream of mTORC1, while eIF4E-binding proteins (4EBP1/2) were suggested to have a general role in translational repression of all transcripts. Here, we use single-molecule translation site imaging of 5′TOP and canonical mRNAs to study the translation of single mRNAs in living cells. Our data reveal that 4EBP1/2 has a dominant role in repression of translation of both 5′TOP and canonical mRNAs during pharmacological inhibition of mTOR. In contrast, we find that LARP1 selectively protects 5′TOP mRNAs from degradation in a transcriptome-wide analysis of mRNA half-lives. Our results clarify the roles of 4EBP1/2 and LARP1 in regulating 5′TOP mRNAs and provide a framework to further study how these factors control cell growth during development and disease.

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“…When permissive conditions return, cells are primed to resume production. Gentilella and colleagues recently proposed a similar “protective” model for Larp1 function that also involve the direct protection of small ribosomal subunits from degradation [ 49 ]. Additionally, the translation-stability link may be a mechanism for buffering the quantity of protein that is produced from each mRNA synthesized.…”

Section: Discussionmentioning

confidence: 99%

mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay

Elzen

¹

,

Watson²,

Thoreen³

2022

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mRNA regulatory sequences control gene expression at multiple levels including translation initiation and mRNA decay. The 5′ terminal sequences of mRNAs have unique regulatory potential because of their proximity to key post-transcriptional regulators. Here we have systematically probed the function of 5′ terminal sequences in gene expression in human cells. Using a library of reporter mRNAs initiating with all possible 7-mer sequences at their 5′ ends, we find an unexpected impact on transcription that underlies 200-fold differences in mRNA expression. Library sequences that promote high levels of transcription mirrored those found in native mRNAs and define two basic classes with similarities to classic Initiator (Inr) and TCT core promoter motifs. By comparing transcription, translation and decay rates, we identify sequences that are optimized for both efficient transcription and growth-regulated translation and stability, including variants of terminal oligopyrimidine (TOP) motifs. We further show that 5′ sequences of endogenous mRNAs are enriched for multi-functional TCT/TOP hybrid sequences. Together, our results reveal how 5′ sequences define two general classes of mRNAs with distinct growth-responsive profiles of expression across synthesis, translation and decay.

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“…When permissive conditions return, cells are primed to resume production. Gentilella and colleagues recently proposed a similar “protective” model for Larp1 function that also involve the direct protection of small ribosomal subunits from degradation [39]. Additionally, the translation- stability link may be a mechanism for buffering the quantity of protein that is produced from each mRNA synthesized.…”

Section: Discussionmentioning

confidence: 99%

mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay

Thoreen

¹

,

Elzen

²

,

Watson

³

2022

Preprint

View full text Add to dashboard Cite

mRNA regulatory sequences control gene expression at multiple levels including translation initiation and mRNA decay. The 5′ terminal sequences of mRNAs have unique regulatory potential because of their proximity to key post-transcriptional regulators. Here we have systematically probed the function of 5′ terminal sequences in gene expression in human cells. Using a library of reporter mRNAs initiating with all possible 7-mer sequences at their 5′ ends, we find an unexpected impact on transcription that underlies 200-fold differences in mRNA expression. Library sequences that promote high levels of transcription mirrored those found in native mRNAs and define two basic classes with similarities to classic Initiator (Inr) and TCT core promoter motifs. By comparing transcription, translation and decay rates, we identify sequences that are optimized for both efficient transcription and growth-regulated translation and stability, including variants of terminal oligopyrimidine (TOP) motifs. We further show that 5′ sequences of endogenous mRNAs are enriched for multi-functional TCT/TOP hybrid sequences. Together, our results reveal how 5′ sequences define two general classes of mRNAs with distinct growth-responsive profiles of expression across synthesis, translation and  decay.

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The 40 S -LARP1 complex reprograms the cellular translatome upon mTOR inhibition to preserve the protein synthetic capacity

Abstract: The mTOR-LARP1-5′TOP axis acts at the translational level as a primary guardian of the anabolic capacity of the cell.

Cited by 16 publications

References 61 publications

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

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

mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay

mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay

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