May 26th, 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, Litsios et al. observe cell cycle-specific dynamics in transcription, translation, and the proteome, Seedhom et al. elucidate translation dynamics during activation of lymphocytes, and Zhang et al. uncover how Epstein-Barr virus suppress immune responses by manipulating RNA modifications.

Proteome-scale movements and compartment connectivity during the eukaryotic cell cycle

Cell, 2024

Athanasios Litsios, Benjamin T. Grys, Oren Z. Kraus, Helena Friesen, Catherine Ross, Myra Paz David Masinas, Duncan T. Forster, Mary T. Couvillion, Stefanie Timmermann, Maximilian Billmann, Chad Myers, Nils Johnsson, L. Stirling Churchman, Charles Boone, Brenda J. Andrews

The authors developed a comprehensive dataset capturing cell cycle-specific dynamics in transcription, translation, and the proteome in budding yeast. By synchronizing cells in G1 phase and isolating them at five subsequent cell cycle phases, they performed RNA sequencing, ribosome profiling, and proteomics analysis on the same samples. Their multi-omics approach revealed that 1,367 transcripts exhibit cell cycle-related periodicity, with only 35% of proteins showing periodic concentration encoded by genes with periodic transcripts. This discrepancy highlights the complex regulation of protein levels, often independent of transcript periodicity.

The authors found that proteins with periodic concentration were predominantly involved in cell cycle control, while those with periodic localization were linked to biophysical processes. A notable observation was the intra-compartmental movement of proteins, such as the FAD transporter Flc1 and Cdc48-interacting protein Ubx6, which altered their local concentrations without changes in overall levels. Additionally, 32 genes showed periodicity across transcript concentration, translational efficiency, and protein concentration, emphasizing multi-level regulation in cell cycle processes.

Functional enrichment analysis revealed that proteins periodic in both concentration and localization had more phosphorylation sites and were likely multifunctional. A detailed study of Ymr295c, a previously uncharacterized protein, showed its dynamic localization and concentration changes during the cell cycle, implicating it in cell wall formation and polarized growth.

This study provides a high-resolution map of proteome dynamics during the cell cycle, integrating systematic genetics, live-cell microscopy, and multi-omics data. The resource offers a foundation for exploring cell cycle regulation and can be extended to study other genetic and environmental conditions, despite limitations in detecting very low-abundance proteins.

Paradoxical imbalance between activated lymphocyte protein synthesis capacity and rapid division rate

eLife, 2024

Mina O Seedhom, Devin Dersh, Jaroslav Holly, Mariana Pavon-Eternod, Jiajie Wei, Matthew Angel, Lucas Shores, Alexandre David, Jefferson Santos, Heather Hickman, Jonathan W Yewdell

This article delves into the intricate mechanisms of protein synthesis in lymphocytes, shedding light on the dynamic processes occurring within these cells. Lymphocytes, upon activation by antigens, undergo rapid division and robust protein synthesis to produce daughter cells armed with immune regulatory and effector molecules. Traditional methods using radiolabeled amino acids hinted at increased protein synthesis upon activation, but newer techniques like ribosome profiling provide deeper insights.

The researchers developed the ribopuromycylation method (RPM) to better quantify active protein synthesis, revealing widespread ribosome stalling in non-activated lymphocytes. Flow-RPM showed a discrepancy in protein synthesis capacity between activated and resting cells. Further experiments using ribosome transit assay (RTA) highlighted differences in elongation rates, suggesting accelerated translation in activated lymphocytes.

In mouse models, ex vivo and in vivo studies elucidated translation dynamics during activation and infection. Results indicated a significant increase in translation upon activation, with potential temperature-dependent variations. Interestingly, monosomes played a substantial role in translation, especially in resting cells.

The study also examined the protein-to-ribosome ratio, crucial for understanding the kinetics of protein synthesis. The discrepancy between observed doubling times and calculated minimal proteome duplication times raised intriguing questions about the mechanisms underlying lymphocyte division and protein synthesis.

The authors point out the complexity of quantifying cellular components accurately, and propose intriguing possibilities such as cells acquiring proteins from others to meet the demands of rapid division. This work underscores the necessity of reconciling theoretical models with experimental data to unravel the intricacies of lymphocyte biology and immunology.

Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion

Journal of Biological Chemistry, 2024

Xiaoyue Zhang, , Zhengshuo Li, Qiu Peng, Can Liu, Yangge Wu, Yuqing Wen, Run Zheng, Chenxiao Xu, Junrui Tian, Xiang Zheng, Qun Yan, Jia Wang, Jian Ma


This work by Zhang et al. delves into the intricate interplay between Epstein-Barr virus (EBV), m6A RNA modification, and Toll-like receptor 9 (TLR9) in the context of EBV-associated malignancies. EBV, a prevalent virus infecting a large portion of the global population, is implicated in various cancers. The study elucidates how EBV infection affects m6A modification profiles of host cells, particularly targeting TLR9, a key innate immune receptor.

EBV employs its nuclear antigen EBNA1 to suppress TLR9 expression via the degradation of METTL3, a component of the m6A methyltransferase complex. This manipulation of m6A levels impacts TLR9 function, potentially aiding EBV in evading immune detection. Additionally, the study uncovers a regulatory role of m6A modification in TLR9 expression, with METTL3 facilitating TLR9 mRNA stability and the m6A “reader” protein YTHDF1 enhancing TLR9 translation.

Moreover, the authors explore the therapeutic implications of these findings. A METTL3 inhibitor, STM2457, demonstrates the ability to suppress TLR9-induced B cell proliferation and antibody secretion, suggesting a potential therapeutic avenue for EBV-associated malignancies. Furthermore, the study highlights the impact of m6A modification on TLR9-mediated antitumor immunity, proposing a mechanism by which inhibition of m6A levels could facilitate immune evasion by tumor cells.

Overall, the study unveils a novel regulatory axis involving EBV infection, m6A modification, and TLR9, shedding light on the complex mechanisms underlying viral oncogenesis and immune evasion. This deeper understanding offers promising prospects for targeted therapeutic interventions in EBV-associated cancers by modulating m6A modification pathways.

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