bims-protra Biomed News
on Proteostasis and translation
Issue of 2025–07–13
three papers selected by
Marius d’Hervé, McGill University



  1. Bioinform Adv. 2025 ;5(1): vbaf134
       Motivation: The 5' untranslated region (5' UTR) of mRNA is crucial for the molecule's translatability and stability, making it essential for designing synthetic biological circuits for high and stable protein expression. Several UTR sequences are patented and widely used in laboratories. This paper presents UTRGAN, a Generative Adversarial Network (GAN)-based model for generating 5' UTR sequences, coupled with an optimization procedure to ensure high expression for target gene sequences or high ribosome load and translation efficiency.
    Results: The model generates sequences mimicking various properties of natural UTR sequences and optimizes them to achieve (i) up to five-fold higher average predicted expression on target genes, (ii) up to two-fold higher predicted mean ribosome load, and (iii) a 34-fold higher average predicted translation efficiency compared to initial UTR sequences. UTRGAN-generated sequences also exhibit higher similarity to known regulatory motifs in regions such as internal ribosome entry sites, upstream open reading frames, G-quadruplexes, and Kozak and initiation start codon regions. In-vitro experiments show that the UTR sequences designed by UTRGAN result in a higher translation rate for the human TNF- α protein compared to the human Beta Globin 5' UTR, a UTR with high production capacity.
    Availability and Implementation: The source code, including the model implementation and the optimization are released at http://github.com/ciceklab/UTRGAN. We downloaded the dataset from the UTRdb 2.0 database and available within the GitHub repository.
    DOI:  https://doi.org/10.1093/bioadv/vbaf134
  2. Cells. 2025 Jun 25. pii: 979. [Epub ahead of print]14(13):
      Heat shock proteins belong to a highly conserved family of chaperone proteins, and in addition to their participation in the regulation of cellular proteostasis (folding of polypeptides and proteins, disaggregation of incorrectly folded peptides, and participation in autophagy processes), also play a significant immunomodulatory role in both innate and adaptive immunity. Changes in the HSP level, both downwards (e.g., in neurodegenerative diseases) and upwards (e.g., autoimmune, oncological diseases), underlie the pathogenesis of many somatic and oncological pathologies. In this review, we consider the main physiological mechanisms of HSP level regulation and also analyze pharmacological, genetically engineered methods of modulating the chaperone level, citing the advantages and disadvantages of a particular method of influence. In conclusion, modulation of the HSP level, according to numerous preclinical studies, can have a significant impact on the course of various pathological conditions, which, in turn, can be used to develop new therapeutic approaches, when the effect on the level of chaperones can be used as monotherapy or as an adjuvant method of action.
    Keywords:  HSF; HSP70; HSP90; biomarker; chaperones; heat shock proteins; inhibitors
    DOI:  https://doi.org/10.3390/cells14130979
  3. bioRxiv. 2025 Jul 03. pii: 2025.07.02.662873. [Epub ahead of print]
      More than 2,700 human mRNA 3'UTRs have hundreds of highly conserved (HC) nucleotides, but their biological roles are unclear. Here, we show that mRNAs with HC 3'UTRs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. These proteins are only fully active when translated from mRNA templates that include their 3'UTRs, raising the possibility of functional interactions between 3'UTRs and IDRs. Rather than affecting protein abundance or localization, we find that HC 3'UTRs control transcriptional or histone demethylase activity through co-translationally determined protein oligomerization states that are kinetically stable. 3'UTR-dependent changes in protein folding require mRNA-IDR interactions, suggesting that mRNAs act as IDR chaperones. These mRNAs are multivalent, a biophysical RNA feature that enables their translation in network-like condensates, which provide favorable folding environments for proteins with long IDRs. These data indicate that the coding sequence is insufficient for the biogenesis of biologically active conformations of IDR-containing proteins and that RNA can catalyze protein folding.
    DOI:  https://doi.org/10.1101/2025.07.02.662873