September 1st, 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, Zhao et al. used ribosome profiling to map the expression of viral and host mRNAs in infectious bronchitis virus. Yang and Thompson used ribosome profiling and RNA sequencing to study miRNA activities in a maize microRNA biogenesis mutant. Lastly, Camarena et al. analysed RNA sequencing, ribosome profiling, and immunopeptidomics data to identify tumor-specific antigens in hepatocellular carcinoma.
Dissecting infectious bronchitis virus-induced host shutoff at the translation level
Journal of Virology, 2024
Zhao, J., Huang, Y., Liukang, C., Yang, R., Tang, L., Sun, L., Zhao, Y. and Zhang, G.
Viruses utilize the host’s translational machinery to facilitate infection, but the methods used by infectious bronchitis virus (IBV) are not fully understood. This study reveals that IBV infection causes a shutoff of host protein synthesis while viral protein production remains unaffected. A screening of 23 viral proteins identified several contributors to this host shutoff, with Nsp15 showing particularly strong inhibitory effects. Using ribosome profiling, the authors mapped the expression of viral and host mRNAs, discovering that IBV mRNAs eventually dominate the cellular mRNA pool despite having lower translation efficiency than cellular mRNAs. Higher densities of RNA-Seq and Ribo-Seq reads were noted in structural proteins and 5′ untranslated regions, aligning with the typical transcriptional patterns of nested viruses.
Post-infection, there was a significant rise in translational halt events and an increased number of paused host genes. These genes were mainly involved in translation, the unfolded protein response, and immune activation pathways. Additionally, mRNAs related to immune and inflammation responses were translated less efficiently in infected cells, resulting in delayed production of interferons IFN-β and IFN-λ. Overall, the findings outline the translational landscape in IBV-infected cells and uncover new strategies by which IBV induces host gene shutoff to promote its replication. This comprehensive understanding of IBV’s manipulation of the host’s translational machinery provides insights into viral infection mechanisms and potential avenues for therapeutic intervention.
Widespread changes to the translational landscape in a maize microRNA biogenesis mutant
The Plant Journal, 2024
Yang, H. and Thompson, B.
MicroRNAs (miRNAs) are short, non-coding RNAs that repress gene expression in plants and animals, playing key roles in growth, development, and stress responses. In plants, the ribonuclease DICER-LIKE1 (DCL1) is essential for miRNA biogenesis, performing two critical cleavage steps: processing primary miRNAs (pri-miRNAs) into a hairpin precursor miRNA (pre-miRNA) and then generating the miRNA/miRNA* duplex from the pre-miRNA. The mature miRNA then guides the RNA-induced silencing complex to target RNAs with complementary sequences, causing translational repression or RNA cleavage. The precise balance between translational repression and mRNA degradation by miRNAs at the genome level, especially in crops like maize, remains unclear. The maize fuzzy tassel (fzt) mutant, which has a hypomorphic mutation in DCL1, exhibits widespread developmental defects and a reduction in most miRNAs.
Despite this reduction, the levels of miRNA-targeted mRNAs do not significantly increase, implying that translational repression may be a common regulatory mechanism. To investigate miRNA repression mechanisms in plants, researchers used ribosome profiling and RNA sequencing to study miRNA activities in maize. The results show that translational repression plays a significant role in how miRNA regulates its mRNA targets, with about one-third of these targets primarily regulated at the translational level. Interestingly, ribosome composition appears altered in fzt mutants, suggesting that DCL1 might also influence ribosome biogenesis. In summary, DICER-LIKE1 shapes the translational landscape in plants through both miRNA-dependent and miRNA-independent pathways, highlighting its multifaceted role in gene regulation and ribosome biogenesis.
Microproteins encoded by noncanonical ORFs are a major source of tumor-specific antigens in a liver cancer patient meta-cohort
Science Advances, 2024
Camarena, M.E., Theunissen, P., Ruiz, M., Ruiz-Orera, J., Calvo-Serra, B., Castelo, R., Castro, C., Sarobe, P., Fortes, P., Perera-Bel, J. and Albà, M.M.
The expression of tumor-specific antigens during cancer progression can elicit an immune response against the tumor. This study explores whether microproteins encoded by noncanonical open reading frames (ncORFs) contribute significantly to tumor-specific antigens. To bypass immune self-tolerance, ncORFs must be expressed specifically in tumors. However, because studies comparing tumor and healthy tissues from the same patients are lacking, it remains uncertain how many previously identified ncORF-derived antigens are truly tumor-specific. Consequently, it is unclear if peptides from ncORFs could serve as effective therapeutic targets. Researchers analyzed RNA sequencing data from 117 hepatocellular carcinoma (HCC) tumors and matched healthy tissues, along with ribosome profiling and immunopeptidomics data.
By integrating human leukocyte antigen–epitope binding predictions and experimental validation, they found that approximately 40% of tumor-specific antigens in HCC likely originate from ncORFs. Notably, two peptides from these ncORFs were shown to provoke an immune response in humanized mice. The study also identified 33 tumor-specific long noncoding RNAs (lncRNAs) that express novel cancer antigens shared by over 10% of the HCC samples analyzed, collectively covering a substantial portion of patients. These findings suggest that ncORFs are a significant source of tumor-specific antigens and propose new targets for anticancer vaccines, potentially broadening the scope of immunotherapy for HCC.