October 15th
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, Sako et al. find that miRNAs play a pivotal role in preventing protein misfolding, Papaspyropoulos et al. explore the variations in translational deregulation across various types of cellular senescence, and Guo et al. review the use of translatomics technologies in the diagnosis and understanding of cancers.
microRNAs slow translating ribosomes to prevent protein misfolding in eukaryotes
The EMBO Journal, 2023
Hiroaki Sako, Mohieldin Youssef, Olga Elisseeva, Takayuki Akimoto, Katsuhiko Suzuki, Takashi Ushida & Tadashi Yamamoto
In this article, Hiroaki Sako et al. explore an intriguing mechanism through which microRNAs (miRNAs) influence protein translation and folding, mitigating the risk of protein misfolding-related diseases in eukaryotic cells.
Proteins often undergo misfolding during translation, which can have severe consequences for cellular function. miRNAs, which are absent in prokaryotes but ubiquitous in eukaryotes, are known to regulate gene expression, however their role in the co-translational folding of proteins was largely unexplored. The researchers employed a comprehensive approach involving ribosome profiling and miRNA binding site analysis. They found that miRNAs, despite their typically weak inhibitory impact on translation, can momentarily halt ribosomes during protein synthesis. This pausing effect, induced by miRNAs binding to coding sequences in mRNA, allows nascent polypeptides the necessary time to fold correctly. Remarkably, this ribosomal stalling occurs with minimal disruption to overall translation efficiency.
To demonstrate the biological significance of this phenomenon, the authors used a misfolding-prone polypeptide reporter. They showed that when global or specific miRNA levels were reduced, ribosomal speed increased, leading to aggregation of the reporter protein. Importantly, they were able to rescue these defects by introducing non-cleaving short hairpin RNAs (shRNAs) that mimicked the action of miRNAs, slowing down ribosomal movement and facilitating proper protein folding.
The study extended its implications to proinsulin, a protein implicated in type 2 diabetes. By designing non-cleaving shRNAs targeting specific regions of insulin genes, the researchers successfully prevented insulin misfolding, offering a promising avenue for potential therapeutic interventions in diseases related to protein misfolding.
Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence
Aging Cell, 2023
Angelos Papaspyropoulos, Orsalia Hazapis, Abdullah Altulea, Aikaterini Polyzou, Panayotis Verginis, Konstantinos Evangelou, Maria Fousteri, Argyris Papantonis, Marco Demaria & Vassilis Gorgoulis
This article explores the translation deregulation patterns associated with different forms of cellular senescence, namely replicative senescence (RS), stress-induced senescence (SIS), and oncogene-induced senescence (OIS). Cellular senescence is characterized by prolonged cell cycle arrest, macromolecular damage, metabolic changes, and a secretory phenotype known as the Senescence-Associated Secretory Phenotype (SASP). While senescence is often linked to aging, it can also result from various stressors and serves as an anti-tumorigenic barrier.
The study uses a combination of computational analysis and experimental validation to investigate translation defects in these senescence types. It reveals distinct translation deregulation mechanisms associated with each form:
Replicative senescence is linked to natural cell aging and exhibits translation deficiency, but without significant translation deregulation patterns like ribosome stalling, upstream open reading frames (uORFs), downstream open reading frames (dORFs), or internal ribosome entry sites (IRES) elements.
Stress-induced senescence induced by oxidative stress shows an increase in translation deficiency accompanied by uORF enrichment. This suggests that uORF-mediated gene regulation is a significant factor in translation defects during oxidative stress-induced senescence.
Oncogene-induced senescence displays the highest level of translation deficiency among the three senescence types and features the most frequent occurrence of all major translation deregulation mechanisms, including ribosome stalling, uORFs, dORFs, and IRES elements. Notably, the Notch signaling pathway is prominently activated in OIS.
The study also experimentally validates these findings using human fibroblast model systems for RS, SIS, and OIS, confirming the presence of distinct translation deregulation patterns in each scenario.
Translatomics to explore dynamic differences in immunocytes in the tumor microenvironment
Molecular Therapy – Nucleic Acids, 2023
Yilin Guo, Shiqi Yan & Wenling Zhang
This comprehensive review delves into the intricate role of mRNA translation in cancer initiation, progression, and the immune response to tumors.
Cancer is characterized by aberrant translation regulation, impacting mRNA, tRNA, ribosomes, and numerous translation factors. Dysregulation of translation initiation factors like EIF4G1, EIF2C2, EIF4E1, and elongation factors such as eEF1A2, eEF1B2, eEF1G, eEF1D, eEF1E1, and eEF2 plays a pivotal role in various cancer types. Oncogenes influence translation through processes like eIF2α phosphorylation and uORF-dependent translation.
Tumorigenesis is associated with changes in tRNA expression and modifying enzymes, synergizing with tRNA overexpression to activate translation. Mitochondrial RNA transcription and translation, as well as altered methylation levels, are linked to cancer. Additionally, miRNA downregulation in cancer affects mRNA abundance and translation efficiency, particularly in tumor suppressor genes.
The application of translatomics in solid tumors has unveiled significant mRNA translation dysregulation, offering potential clinical markers and therapeutic targets. In the tumor microenvironment (TME) various immune cells including T lymphocytes, B lymphocytes, macrophages, dendritic cells, and natural killer cells, exhibit distinct translation profiles. These profiles profoundly influence immune responses and tumor outcomes.
Translatomics technologies are invaluable for diagnosing cancer, understanding its etiology and prognosis, predicting treatment responses, and identifying drug targets. This comprehensive insight into translation regulation in cancer and the TME provides a foundation for tailored cancer therapies and opens new avenues for improving patient outcomes.