bims-protra 2025-08-03 papers

Issue of 2025–08–03
four papers selected by
Marius d’Hervé, McGill University

Nat Biotechnol. 2025 Jul 25.

Predicting the translation efficiency of messenger RNA in mammalian cells.

Dinghai Zheng, Logan Persyn, Jun Wang, Yue Liu, Fernando Ulloa-Montoya, Can Cenik, Vikram Agarwal.

The mechanisms by which mRNA sequences specify translational control remain poorly understood in mammalian cells. Here we generate a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing more than 140 human and mouse cell types from 3,819 ribosomal profiling datasets. We develop RiboNN, a state-of-the-art multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features. While most earlier models solely considered the 5' untranslated region (UTR) sequence, RiboNN integrates how the spatial positioning of low-level dinucleotide and trinucleotide features (that is, including codons) influences TE, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN predicts the translational behavior of base-modified therapeutic RNA and explains evolutionary selection pressures in human 5' UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability and localization in mammalian organisms.

DOI: https://doi.org/10.1038/s41587-025-02712-x

RNA. 2025 Jul 31. pii: rna.080493.125. [Epub ahead of print]

40S ribosomal subunits scan mRNA for the start codon by one-dimensional diffusion.

Hironao Wakabayashi, Mingyi Zhu, Elizabeth J Grayhack, David H Mathews, Dmitri N Ermolenko.

During eukaryotic translation initiation, the small (40S) ribosomal subunit is recruited to the 5' cap and subsequently scans the 5' untranslated region (5' UTR) of mRNA in search of the start codon. The molecular mechanism of mRNA scanning remains unclear, particularly the requirement for and identity of a translocase. Here, using GFP reporters in Saccharomyces cerevisiae, we show that order-of-magnitude variations in the length of unstructured 5' UTRs have only modest effects on protein synthesis, while structured 5' UTRs strongly inhibit translation. Thus, when not hindered by secondary structure, mRNA scanning is not rate limiting. Loss-of-function mutations in eIF4A, Ded1 and Slh1 reveal that these translational helicases are dispensable for mRNA scanning. Our data suggest that one-dimensional diffusion predominately enables 40S movement along the 5' UTR during mRNA scanning.

Keywords: mRNA scanning; one-dimensional diffusion; ribosome; translation initiation

DOI: https://doi.org/10.1261/rna.080493.125

Biochim Biophys Acta Mol Cell Res. 2025 Jul 24. pii: S0167-4889(25)00132-6. [Epub ahead of print] 120027

Heat shock protein 70 regulates m6A modification in response to heat shock in esophageal squamous cell carcinoma.

Bin Du, Jia Wang, Jun Ma, Pu Wang.

Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that the severely lacking of m6A 'writer' components of ESCC cells exhibit higher apoptosis rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.07 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these genes. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.

Keywords: Esophageal squamous cell carcinoma; HSP70; Heat shock; METTL3/14 complex; m6A

DOI: https://doi.org/10.1016/j.bbamcr.2025.120027

Nat Commun. 2025 Jul 26. 16(1): 6906

A complex between IF2 and NusA suggests early coupling of transcription-translation.

Mikhail Metelev, Magnus Johansson.

The main function of translation initiation factors is to assist ribosomes in selecting the correct reading frame on an mRNA. This process has been extensively studied with the help of reconstituted in vitro systems, but the dynamics in living cells have not been characterized. In this study, we performed single-molecule tracking of the bacterial initiation factors IF2, IF3, as well as the initiator fMet-tRNAfMet directly in growing Escherichia coli cells. Our results reveal the kinetics of factor association with the ribosome and, among other things, highlight the respective antagonistic roles of IF2 and IF3 in the process. Importantly, our comparisons of in vivo binding kinetics of two naturally occurring isoforms of IF2 reveal that the longer IF2α isoform directly interacts with the transcriptional factor NusA, a finding further corroborated by pull-down and cross-linking experiments. Our results suggest that this interaction may promote formation of a coupled transcription-translation complex early in the translation cycle, motivating further structural studies to validate the mechanism. We further show that cells with compromised binding between IF2α and NusA display slow adaptation to new growth conditions.

DOI: https://doi.org/10.1038/s41467-025-62207-w