August 11th, 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 week’s Sunday papers, Lin et al. unveils that histone deacetylase Hos2 regulates protein expression noise by modulating the translation machinery in yeast. Rodriguez et al. discovered that 5’ untranslated region can also be translated into functional peptides. Takada et al. presented the mechanisms of elongation factor P and ABCF ATPases YfmR and YkpA/YbiT in resolving ribosomal stalling in Bacillus subtilis, of which the arrest is crucial for protein synthesis and cell survival.
Histone deacetylase Hos2 regulates protein expression noise by potentially modulating the protein translation machinery
Nucleic Acid Research, 2024
Lin, W.H., Opoc, F.J., Liao, C.W., Roy, K.R., Steinmetz, L.M. and Leu, J.Y.
This paper investigates the role of Hos2, a histone deacetylase, in regulating protein expression noise in Saccharomyces cerevisiae. Protein expression noise refers to the variability in protein levels among genetically identical cells, which can lead to heterogeneity within a cell population.
The study reveals that Hos2 functions as a negative regulator of protein expression noise. Mutant strains of yeast lacking Hos2 exhibited increased variability in protein expression, suggesting that Hos2 helps maintain uniform protein levels across cells. The researchers found that the absence of Hos2 led to the downregulation of multiple ribosomal protein genes, which are essential for protein synthesis. This downregulation compromised the protein translation machinery, indicating that Hos2 may regulate expression noise by influencing the efficiency and consistency of protein translation.
The researchers employed an experimental evolution strategy to identify mutations that increase expression noise, followed by genetic and biochemical analyses to confirm their findings. By using polysome profiling, translation inhibitors and introducing mutations in ribosomal protein genes regulated by Hos2, the authors demonstrated the connection between Hos2 activity and the protein translation machinery.
This study underscores the importance of histone modifications in controlling not only the levels of gene expression but also the variability of expression. The findings suggest that disruptions in the regulation of protein expression noise by histone deacetylases like Hos2 could contribute to diseases characterised by abnormal protein expression variability.
Evidence for widespread translation of 5′ untranslated regions
Nucleic Acid Research, 2024
Rodriguez, J.M., Abascal, F., Cerdán-Vélez, D., Gómez, L.M., Vázquez, J. and Tress, M.L.
Rodriguez et al. provide compelling insights into the active translation of 5′ untranslated regions (5′ UTRs) in gene expression. Traditionally, 5′ UTRs were thought to function primarily in regulating the efficiency and stability of mRNA translation. However, this study demonstrates that 5′ UTRs can also be translated into functional peptides, challenging this traditional view.
Ribosome profiling data from various eukaryotic species show extensive ribosome occupancy in 5′ UTRs, indicating the presence of upstream open reading frames (uORFs) that are actively translated. This translation can regulate the main coding sequence (mORF) translation through mechanisms like ribosome stalling, which in turn affects protein synthesis in response to cellular conditions. Some of the peptides encoded by these uORFs have been found to possess regulatory functions. For instance, a peptide encoded within a 5′ UTR was shown to promote pain sensitization in mice, illustrating a physiological role and potential involvement in disease states.
Moreover, the evolutionary conservation of uORFs in 5′ UTRs suggests that their translation is functionally significant and has been maintained across different species. This finding underscores the complexity and regulatory potential of 5′ UTRs, positioning them as a rich source of regulatory elements. Understanding the translation of 5′ UTRs opens up new avenues in biotechnology and medicine, potentially leading to novel therapeutic strategies targeting these regions to modulate protein expression.
Overall, this research not only redefines the functional landscape of 5′ UTRs but also emphasizes their importance in the regulation of gene expression and protein synthesis.
Resolution of ribosomal stalling by EF-P and ABCF ATPases YfmR and YkpA/YbiT
Nucleic Acid Research, 2024
Takada, H., Fujiwara, K., Atkinson, G.C., Chiba, S. and Hauryliuk, V.
Ribosomal stalling occurs when the ribosome encounters sequences in mRNA that are difficult to translate, such as polyproline tracts. This stalling can impede protein synthesis and cell growth. This paper by Takada et al. explores the mechanisms by which Bacillus subtilis manages ribosomal stalling, a critical issue in protein synthesis.
The study highlights the roles of elongation factor P (EF-P) and the ATP-binding cassette F (ABCF) ATPases YfmR and YkpA/YbiT in resolving these stalls. EF-P is known to alleviate stalling at polyproline sequences, facilitating their translation. The researchers found that YfmR, an ABCF ATPase, works in concert with EF-P to further enhance the translation of these challenging sequences.
Through genetic and biochemical analyses, the study demonstrates that the simultaneous loss of both EF-P and YfmR leads to significant growth defects in B. subtilis. This defect is characterized by severe ribosomal stalling and reduced levels of actively translating ribosomes. Interestingly, overexpression of another translation factor can partly compensate for the loss, indicating a complex network of factors involved in maintaining translation efficiency.
Moreover, the research reveals that YfmR associates with actively translating ribosomes and is crucial for the proper function of the ribosome in the absence of EF-P. Depletion of YfmR from cells lacking EF-P leads to lethal outcomes, underscoring its essential role in translation under these conditions.
This study advances our understanding of the molecular mechanisms behind ribosomal stalling and highlights the importance of ABCF ATPases in bacterial translation, suggesting potential targets for antimicrobial development.