July 14th, 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, Kim et al. induced stress on the eIF4F complex to investigate its function in modulating gene expression to promote cellular survival. Musaev et al. showed that Upf1 destablised mRNAs with suboptimal codon usage and containing uORFs to degrade them for the fidelity of gene expression. Kurihara et al. described that 3-bromo-7-nitroindazole (3B7N) was used to control Arabidopsis growth in crops by inducing shade-avoidance syndrome to affect its traits.
eIF4F complex dynamics are important for the activation of the integrated stress response
Molecular Cell, 2024
Kim, K.Q., Nanjaraj Urs, A.N., Lasehinde, V., Greenlaw, A.C., Hudson, B.H. and Zaher, H.S.
The eIF4F complex, which includes eIF4E, eIF4A, and eIF4G, is crucial for the regulation of translation initiation under stress conditions. Stress conditions led to the phosphorylation of eIF2α, a key event in activating the ISR, which promoted the translation of specific mRNAs that help Saccharomyces cerevisia cope with stress.
Ribosome profiling was utilised to identify that the loss of eIF4E caused the translation of GCN4 in the absence of cap recognition, which was triggered by the temperature-sensitive allele of eIF4E, in S. cerevisiae. The technique revealed that the factor degraded rapidly under repressive condition at 37°C. The profiling revealed that stress led to selective translation of certain pro-survival genes, such as GCN4 in yeast. Depletion of eIF4E led to a unique mode of translational control, bypassing the need for eIF2α phosphorylation. This reflects an alternative regulatory mechanism when at stress. eIF4A, which may facilitate faster scanning by ribosomes, contributed to the de-repression of translation of GCN4, highlighting the importance of eIF4F complex components in modulating translation under stress.
Under stress conditions, there was a notable accumulation of inactive 80S monosomes, which indicated a general inhibition of translation initiation. Polysome profiling indicated a depletion of ribosomes from polysomes, confirming that translation initiation was significantly impaired under stress. Alterations in eIF4F complex dynamics were linked to changes in translation factor concentrations in certain cancers, providing insights into potential therapeutic targets. These findings emphasised the importance of eIF4F dynamics in managing cellular stress responses and suggested new avenues for research into stress-related diseases and cancer therapies.
UPF1 regulates mRNA stability by sensing poorly translated coding sequences
Cell Reports, 2024
Musaev, D., Abdelmessih, M., Vejnar, C.E., Yartseva, V., Weiss, L.A., Strayer, E.C., Takacs, C.M. and Giraldez, A.J.
Upf1 is a protein primarily known for its involvement in nonsense-mediated mRNA decay (NMD). The study revealed that Upf1 regulated mRNA stability by identifying and targeting mRNAs with inefficient translation.
Musaev et al. demonstrated that Upf1 selectively bound to poorly translated mRNAs, which was identified by suboptimal codon usage or weak Kozak sequences. Ribosome profiling helped in pinpointing mRNAs with suboptimal translation, characterised by fewer ribosome footprints, which were then targeted by UPF1 for degradation. Upf1 destabilised the poorly translated mRNAs, as well as those containing upstream open reading frames (uORFs). The binding of Upf1 is independent of the 3′ untranslated region (UTR) length but relies on the translational status of the mRNA. The decay mechanism ensures the degradation of aberrantly translated mRNAs, thereby maintaining the fidelity of gene expression and preventing the accumulation of defective proteins.
Upf1’s activity and specificity are regulated by its phosphorylation state, affecting its binding affinity and decay induction. By targeting poorly translated mRNAs, Upf1 ensures the fidelity of gene expression and prevents the accumulation of defective proteins. Musaev et al. proposed a novel pathway termed ORF-mediated decay (OMD), which is unlike the traditional exon-junction complex (EJC)-dependent NMD pathway. OMD involves Upf1 recognizing and degrading mRNAs based solely on their translation efficiency and structural features without relying on EJCs. It provides a more comprehensive mechanism for mRNA surveillance and quality control.
Fundamentally, the authors’ findings extended our understanding of mRNA surveillance and cellular homeostasis. Upf1 helped maintain protein quality and prevented the accumulation of defective proteins, which could lead to cellular dysfunction or disease, such as NMD. The study underscored the importance of translation efficiency in mRNA stability and opens new avenues for exploring how cells regulate gene expression at the post-transcriptional level.
The blue light signalling inhibitor 3-bromo-7-nitroindazole affects gene translation at the initial reception of blue light in young Arabidopsis seedlings
Plant Biotechnology, 2024
This study explored the role of the blue light signalling inhibitor 3-bromo-7-nitroindazole (3B7N) on gene translation in young Arabidopsis seedlings. Building on previous findings that 3B7N inhibits blue light-mediated suppression of hypocotyl elongation by interacting with the blue light receptor Cryptochrome 1 (CRY1), the authors used RNA sequencing (RNA-seq) and ribosome profiling (Ribo-seq) to investigate genome-wide gene expression and translation changes in seedlings exposed to blue light.
Key findings reveal that 3B7N negatively impacts the translation of ribosome-related genes, with effects like those observed in cry1cry2 mutants and plants with suppressed photosynthesis, suggesting a complex interaction between chloroplast function and blue light signalling. The inhibition of blue light signalling delayed chloroplast formation and reduced energy supply, affecting translation. The study proposes that 3B7N disrupts the normal translation processes triggered by blue light, highlighting significant crosstalk between nuclear and chloroplastic signalling pathways.
By using translatomics tools, the study elucidates how specific inhibitors can modulate translational dynamics in plants. It underscores the intricate relationship between light signalling, gene expression, and protein synthesis, enhancing our understanding of the molecular mechanisms underlying light perception and response in plant development. The findings also open new avenues for exploring the regulatory networks linking light signalling with chloroplast function and gene translation. The study highlights the potential for using chemical treatments like 3B7N to control plant growth in crops, potentially inducing shade-avoidance syndrome to affect traits such as stem elongation and flowering, especially in crops resistant to genetic modification.