February 18th, 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, Mansouri-Noori et al. investigate the role of Slr1p in regulating mRNA translation and decay in S. pombe. Gurung et al. look at development of a pioneering platform for the identification and application of tumor-associated neoepitopes for cancer immunotherapies, and lastly, Zafirov et al. study the intricate molecular interplay between Arabidopsis thaliana and Turnip mosaic virus (TuMV).
The LARP1 homolog Slr1p controls the stability and expression of proto-5′ TOP mRNAs in fission yeast.
Cell Reports, 2023
Mansouri-Noori, F., Pircher, A., Bilodeau, D., Siniavskaia, L., Grigull, J., Rissland, O.S. and Bayfield, M.A.
This study investigates the role of Slr1p, a Schizosaccharomyces pombe homolog of the La-related protein 1 (LARP1), in regulating mRNA translation and decay, focusing on ribosomal protein (RP) mRNAs similar to 5′ TOP mRNAs in more complex organisms. By integrating proteomic and transcriptome-wide analyses, the research uncovers Slr1p’s interactions with key factors in translation and mRNA decay, such as eIF4G, eIF3i, and Exo2p, revealing how Slr1p promotes RP mRNA stability and abundance. This challenges previous views on the LARP1 family’s function and indicates a sophisticated regulatory mechanism.
The absence of Slr1p was found to hinder translation initiation, leading to decreased heavy polysome levels and increased 80S monosome formation, a sharp contrast to cells with Slr1p, which show stable translation. Additionally, Slr1p’s presence boosts co-translational mRNA decay through enhanced recruitment of Exo2p to translation complexes.
Further findings emphasize Slr1p’s specific interaction with AC-rich motifs in the 5′ UTRs of RP mRNAs, illustrating its precise regulatory role. This specificity, alongside Slr1p’s context-dependent functionality under various environmental and stress conditions, suggests a more complex regulatory framework than previously understood.
Overall, this research enriches our comprehension of mRNA regulation, highlighting the conserved function of the LARP1 family across eukaryotes. It sets the stage for future exploration into how Slr1p differentially regulates RP mRNA metabolism in response to changing biological conditions, offering insights into the nuanced control of gene expression at the translational level.
Systematic discovery of neoepitope–HLA pairs for neoantigens shared among patients and tumor types.
Nature Biotechnology, 2023
Gurung, H.R., Heidersbach, A.J., Darwish, M., Chan, P.P.F., Li, J., Beresini, M., Zill, O.A., Wallace, A., Tong, A.J., Hascall, D. and Torres, E.
This research introduces a pioneering platform designed to enhance the identification and application of tumor-associated neoepitopes for cancer immunotherapies. Addressing the challenge posed by the limited variety of neoepitopes recognized across different patients or cancer types, the study integrates a high-throughput peptide-HLA binding assay with cellular models engineered to express specific HLA types and a transgene containing 47 frequently occurring cancer neoantigens. Through screening over 24,000 neoepitope-HLA combinations, 844 unique possibilities were identified, with 86 confirmed via mass spectrometry analysis in cell lines expressing a single HLA allele.
Additionally, the study explores translational efficiency using ribosome profiling of a 47-mer polyantigen transgene, revealing that the inclusion of linkers in the transgene design significantly reduces translation efficiency after the first 20 neoantigen sequences. This insight into the translation process of neoepitopes emphasizes the necessity of optimizing transgene design to improve neoantigen expression and presentation, offering valuable tools and data for advancing antigen processing and neoepitope targeting therapies.
Collectively, the findings highlight the critical role of both innovative platform development and translational studies in broadening the scope of effective cancer immunotherapies through enhanced identification and utilization of neoepitopes.
Arabidopsis eIF4E1 protects the translational machinery during TuMV infection and restricts virus accumulation
PLOS Pathogens, 2023
In this comprehensive study, the authors investigated the intricate molecular interplay between Arabidopsis thaliana and Turnip mosaic virus (TuMV), shedding light on the host’s translation initiation factors and their impact on virus susceptibility. The research focused on two key players: eIF4E1 and eIFiso4G1. The results showed that TuMV infection triggers the degradation of eIFiso4G1, a scaffolding protein crucial for the eIFiso4F translation initiation complex. This degradation led to decreased global plant translation but increased TuMV multiplication, uncovering a novel strategy employed by the virus to hijack the host’s translational machinery.
Furthermore, the authors explored the functional consequences of eIFiso4G1 degradation by analyzing Arabidopsis knock-outs for both eIF4E1 and eIFiso4G1. The absence of eIFiso4G1 alone did not significantly impact TuMV disease symptoms, but concurrent loss of eIF4E1 exacerbated the severity of symptoms, including stunted growth and tissue senescence, leading to plant death in some cases. Interestingly, TuMV accumulation was reduced in the absence of eIFiso4G1 alone, emphasizing its role in supporting optimal virus multiplication.
The study elucidated a delicate balance between the eIF4F and eIFiso4F complexes in regulating host translation and potyvirus infection susceptibility. The findings not only provided insights into TuMV’s interaction with the plant’s translation apparatus but also raised questions about the potential involvement of eIFiso4G2 and the intricate mechanisms behind disease symptoms development. This research provides valuable insight for designing effective genetic resistances against plant viruses based on translation initiation factor manipulation.