December 22nd, 2024
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this weekโs Sunday papers, Malik et al. find that disrupting tRNA biogenesis enhances proteostasis, health span, and longevity across species. Ly et al. show that nuclear eIF1 release during mitosis increases start-codon fidelity, safeguarding proteome integrity. Li et al. reveal how Plasmodium falciparum adapts its tRNA regulation and translation to nutrient stress for survival within red blood cells.
Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity
PLOS Biology, 2024
Malik, Y., Kulaberoglu, Y., Anver, S., Javidnia, S., Borland, G., Rivera, R., Cranwell, S., Medelbekova, D., Svermova, T., Thomson, J., Broughton, S., von der Haar, T., Selman, C., Tullet, J.M.A. and Alic, N.
This paper investigates the impact of reduced RNA polymerase III (Pol III) activity on tRNA levels and its subsequent effects on aging and proteostasis across multiple species. Pol III is responsible for transcribing tRNAs and other short noncoding RNAs.
RNA-seq revealed that partial inhibition of Pol III activity led to a significant disruption in tRNA levels in C. elegans, D. melanogaster, and mice. Notably, other Pol III-transcribed RNAs, such as 5S rRNA and 7SL RNA, remained largely unaffected, indicating a selective impact on tRNA biogenesis.
The reduction in tRNA levels was associated with increased resistance to proteostatic stress. In C. elegans, this was evidenced by the activation of the unfolded protein response (UPR), suggesting an improved capacity to manage misfolded proteins. In D. melanogaster, a loss-of-function mutation in the TFIIIC transcription factor, which reduces Pol III initiation on tRNA genes, significantly extended lifespan. The flies carrying the mutation also exhibited enhanced proteostatic resilience and broad-spectrum improvements in late-life health.
Ribo-seq analysis in D. melanogaster revealed that partial RNA Pol III inhibition lead to differential translation of over 400 mRNAs, including increased translation of Caliban mRNA, which plays a role in proteostasis.
In summary, the selective reduction of tRNA levels through partial Pol III inhibition enhances the organism’s ability to cope with proteotoxic stress, thereby improving late-life health and extending lifespan in model organisms.
Nuclear release of eIF1 restricts start-codon selection during mitosis
Nature, 2024
Ly, J., Xiang, K., Su, K.-C., Sissoko, G.B., Bartel, D.P. and Cheeseman, I.M.
This paper investigates how translation initiation is regulated during mitosis to maintain proteome integrity. The researchers discovered that during mitosis, the stringency of start-codon selection increases, leading to repression of low-efficiency initiation sites. This results in widespread changes in the translation of thousands of start sites and their corresponding protein products.
Ribo-seq analysis using harringtonine, a compound that stalls ribosomes at translation initiation sites, paired with RNA-seq, revealed transcriptome-wide changes in translational start site usage between interphase and mitosis in HeLa cells. During mitosis, the use of non-AUG codons and weak Kozak contexts was markedly reduced, indicating enhanced fidelity in start-codon selection.
Polysome profiling and fraction collection was used to isolate 40S, 60S, and 80S fractions from interphase and mitotically arrested cells. Mass spectrometry analysis of these fractions revealed a mitosis-specific enrichment of eIF1 in the 40S subunit, while eIF5 was depleted. eIF1 increases the stringency of start codon selection, whereas eIF5 decreases stringency. Despite unchanged global eIF1 and eIF5 levels between the two conditions, eIF1 was primarily located within the nucleus during interphase, butย relocated the cytoplasm during mitosis.
Furthermore, the study demonstrates that preventing this mitotic translational control increases cell death and decreases mitotic slippage in cells subjected to anti-mitotic chemotherapies. This suggests that the regulation of translation initiation stringency during mitosis is crucial for cell survival under stress.
In summary, the research highlights a novel mechanism by which cells control translation initiation during mitosis through the regulated localization of eIF1, ensuring proteome fidelity and proper cell cycle progression.
tRNA regulation and amino acid usage bias reflect a coordinated metabolic adaptation in Plasmodium falciparum
iScience, 2024
Li, Q., Vetter, L., Veith, Y., Christ, E., Vรฉgvรกri, ร., Sahin, C., Ribacke, U., Wahlgren, M., Ankarklev, J., Larsson, O. and Chan, S.C.-L.
Plasmodium falciparum, a protozoan responsible for malaria, infects red blood cells (RBCs) and relies on metabolic adaptations to thrive within its host environment. This study explores the parasite’s strategies for amino acid utilization, focusing on tRNA regulation, mRNA expression, and translational control under nutrient stress. Using a tailored tRNA-seq protocol, the researchers observed that tRNAs decoding amino acids that are rare in hemoglobin (HB) are disproportionately underrepresented relative to their codon demand. This mismatch affects translational elongation efficiency, creating a bottleneck during the synthesis of proteins that require these amino acids.
RNA-seq revealed that highly expressed transcripts are biased toward amino acid compositions resembling those abundant in HB, minimizing their reliance on external nutrient sources. Conversely, transcripts encoding proliferation-related proteins demand HB-scarce amino acids, making their translation more sensitive to nutrient stress.
Polysome profiling under amino acid-depleted conditions showed reduced polysome formation, increased 80S monosome accumulation, and ribosome stalling at isoleucine-rich codons. mRNAs with weak initiation contexts exhibited stabilization during nutrient stress, while those with stronger initiation signals experienced destabilization, likely due to ribosome collisions.
This coordinated regulation suggests that P. falciparum exploits its tRNAome and codon bias to modulate gene expression dynamically, ensuring proteome stability during nutrient fluctuations. The study highlights a novel mechanism linking translation elongation to transcript stability, enabling adaptive transcriptome reprogramming in response to metabolic constraints.