bims-protra 2025-08-24 papers

Issue of 2025–08–24
two papers selected by
Marius d’Hervé, McGill University

Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102648

Evaluation of synthetic mRNA with selected UTR sequences and alternative poly(A) tail, in vitro and in vivo.

Ayoub Medjmedj, Hugo Genon, Dounia Hezili, Albert Ngalle Loth, Rudy Clemençon, Cyril Guimpied, Lucile Mollet, Anne Bigot, Frank Wien, Josef Hamacek, Clément Chapat, Federico Perche.

Messenger RNA (mRNA) has emerged as an attractive new technology of drugs. The efficacy of mRNA technology depends on both the efficiency of mRNA delivery and translation. Untranslated regions (UTRs) and the poly(A) tail play a crucial role in regulating mRNA intracellular kinetics. Intending to improve the therapeutic potential of synthetic mRNA, we evaluated various UTRs and tail designs, using Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine sequences as a reference. First, we screened six 5' UTRs (cap-dependent/-independent), evaluated nine 5' UTR-3' UTR combinations, and a novel heterologous A/G tail in cell models, and in vivo using luciferase as a reporter gene. Then, to decipher the translation mechanism of selected UTRs, we correlated mRNA expression with ribosome load, mRNA half-life, mRNA immunogenicity, and UTR structures. Our results showed that the heterologous tail we introduced is as potent as the Pfizer-BioNTech tail and confirmed the high potency of the human α-globin 5' UTR. They also revealed the potential of the VP6 and SOD 3' UTRs. We validated our results using mRNA encoding the SARS-CoV-2 spike protein formulated as lipid nanoparticles (LNPs) for mouse immunization. Overall, the selected 3' UTRs and heterologous A/G tail have great potential as new elements for therapeutic mRNA design.

Keywords: 3′ UTR; 5′UTR; MT: Oligonucleotides: Therapies and Applications; mRNA; mRNA stability; poly(A) tail; translation efficiency; vaccine

DOI: https://doi.org/10.1016/j.omtn.2025.102648

Cell Stress Chaperones. 2025 Aug 15. pii: S1355-8145(25)00054-9. [Epub ahead of print]30(5): 100109

Multifaceted roles of mammalian heat shock factor 1 in the central nervous system.

Nicholas B Rozema, Rocio Gomez-Pastor.

Heat shock factor 1 (HSF1) is a stress-protective transcription factor most associated with transcriptional regulation of genes involved thermal stress response and protein folding. The canonical activation cycle of HSF1, in which HSF1 recognizes a simple promoter binding site known as a heat shock element (HSE) to promote the transcription of molecular chaperones, has been well documented. However, it is now evident that mammalian HSF1 exhibits unexpected complexity and participates in the response to a vast array of cellular stress types. The versatility of HSF1 can be attributed to distinct local protein concentrations, posttranslational modifications (PTMs), and binding partners found in different anatomical regions of the mammalian system. Advances in our knowledge of HSF1 under different types of stress have illuminated its vast array of gene targets, ranging from protein folding to mitochondrial homeostasis to cytoskeletal stability and beyond. In this review, we explore current knowledge of mammalian HSF1 and its gene targets within the central nervous system. While HSF1 has been extensively studied in the context of neurodegeneration, our understanding of its diverse roles in this setting remains limited. We also highlight emerging evidence supporting a physiological role for HSF1 in the healthy brain, an area that has received relatively little attention. Advancing a more comprehensive understanding of HSF1 function in the mammalian brain may aid in the development of novel therapeutics aimed at alleviating symptoms across a range of neurological disorders.

Keywords: Brain; Cellular stress; HSF1; Neurodegeneration; Synaptic stability

DOI: https://doi.org/10.1016/j.cstres.2025.100109