April 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, Andjus et al. (2024) use ribosome profiling to confirm ribosome binding to Xrn1-sensitive lncRNAs and identify actively translated 5’-proximal small ORFs in yeast. Dagar et al. (2024) employ ribosome profiling to examine detailed ribosome occupancy of mitochondrial mRNA transcripts in both control and Huntington’s Disease striatal cell models. Lastly, Shin et al. (2024) show that a quality control pathway, known as CENTRE, ensures proper targeting of the RNC–SRP complex to the ER by repressing translation until transport is initiated.

Pervasive translation of Xrn1-sensitive unstable long non-coding RNAs in yeast

RNA, 2024

Andjus, S., Szachnowski, U., Vogt, N., Gioftsidi, S., Hatin, I., Cornu, D., Papadopoulos, C., Lopes, A., Namy, O., Wery, M. and Morillon, A.

Long non-coding RNAs (lncRNAs), previously thought to lack coding potential, can associate with ribosomes, some of which are now acknowledged as significant RNA regulators involved in various cellular processes. Their expression is meticulously regulated, reflecting their functional importance, and aberrant lncRNA expression has been linked to human diseases such as cancers. Despite this, there is limited understanding of the extent and biological importance of lncRNA translation. In yeast, cytoplasmic Xrn1-sensitive lncRNAs called XUTs undergo degradation through a process involving nonsense-mediated mRNA decay (NMD), hinting at translation-dependent degradation. In this study, the authors demonstrate that XUTs are actively translated, affecting their degradation.

When translation elongation is inhibited, XUTs accumulate globally, but not when ribosome loading is hindered initially. The study uses ribosome profiling to confirm ribosome binding to XUTs with a characteristic 3-nt periodicity – a signature for translation. Additionally, they identified actively translated 5’-proximal small ORFs. The sensitivity of XUTs to NMD depends largely on the length of their 3’ untranslated regions. Additionally, the translation of an NMD-sensitive XUT reporter generates a peptide that exists in cells that are capable of NMD. Overall, the findings emphasize the significance of translation in regulating the fate of XUTs post-transcriptionally, suggesting that the peptides produced from XUTs could undergo natural selection while NMD restricts XUT levels.

Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease

Molecular & Cellular Proteomics, 2024

Dagar, S., Sharma, M., Tsaprailis, G., Tapia, C.S., Crynen, G., Joshi, P.S., Shahani, N. and Subramaniam, S.

Huntington’s disease (HD) results from an expanded polyglutamine mutation in the huntingtin gene, mHTT, leading to significant atrophy in the striatum and subsequent psychiatric, cognitive, and involuntary movements. Numerous studies suggest a link between HD and abnormal mitochondrial function in the striatum. However, it is not well understood whether or how mitochondrial mRNA translation is specifically affected in HD. Dagar et al. employed ribosome profiling to examine detailed ribosome occupancy of mitochondrial mRNA transcripts in both control and HD striatal cell models. This study reveals decreased protein synthesis in HD mitochondria compared to healthy control striatal cell models.

The Ribo-Seq data showed minimal changes in ribosome binding to nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS) in HD cells. In contrast, there was a significant increase in ribosome occupancy in mitochondrially encoded OXPHOS mRNAs. They also employed tandem mass tag–based mass spectrometry to identify mitochondrial proteins and correlate ribosome binding with actual mature mitochondrial protein products. Their findings revealed many mitochondrial transcripts with similar or higher ribosome binding but reduced levels of mature mitochondrial proteins in HD. This indicates a widespread discrepancy between ribosome binding and protein production in mitochondria-related genes in HD, representing the first reporting of such a phenomenon.

Nonsense-mediated mRNA decay of mRNAs encoding a signal peptide occurs primarily after mRNA targeting to the endoplasmic reticulum

Molecules and Cells, 2024

Shin, M.K., Chang, J., Park, J., Lee, H.J., Woo, J.S. and Kim, Y.K.

 

The process of translating mRNAs that encode integral membrane proteins or secreted proteins occurs on the surface of the endoplasmic reticulum (ER). The ribosome-nascent chain complex (RNC) is recognized by the signal recognition particle (SRP) and transported to the ER when a nascent signal peptide is synthesized. Once the CBC–RNC–SRP complex reaches the ER surface, it engages with the SRP receptor (SR), consisting of SRα and SRβ. This interaction causes the dissociation of CBP80 from SRP54, transitioning the complex to eIF4E–RNC–SRP with the aid of importin-β, thereby lifting translational inhibition. Subsequently, the mRNA’s 5′-cap bound by eIF4E becomes available for small ribosomal subunit scanning.

The quality control pathway, known as CENTRE, ensures proper targeting of the RNC–SRP complex to the ER by repressing translation until transport is initiated. Using ribosome profiling, the study reveals that CENTRE operates on a transcriptome-wide level to guarantee the accurate expression of mRNAs that encode signal peptides. Moreover, CENTRE inhibits nonsense-mediated mRNA decay (NMD) until the RNC–SRP complex is targeted to the ER and replaced by eIF4E. This indicates a dual surveillance mechanism for targeting mRNAs to the ER, where CENTRE regulates translation before ER targeting, while NMD monitors mRNA quality after ER delivery.

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