bims-hypusi 2025-02-16 papers

Issue of 2025–02–16
four papers selected by
Sebastian J. Hofer, University of Graz

PLoS One. 2025 ;20(2): e0308049

Development of a reliable, sensitive, and convenient assay for the discovery of new eIF5A hypusination inhibitors.

Oumayma Benaceur, Paula Ferreira Montenegro, Michel Kahi, Fabien Fontaine-Vive, Nathalie M Mazure, Mohamed Mehiri, Frederic Bost, Pascal Peraldi.

eIF5A is a translation factor dysregulated in several pathologies such as cancer and diabetes. eIF5A activity depends upon its hypusination, a unique post-translational modification catalyzed by two enzymes: DHPS and DOHH. Only a few molecules able to inhibit hypusination have been described, and none are used for the treatment of patients. The scarcity of new inhibitors is probably due to the challenge of measuring DHPS and DOHH activities. Here, we describe the Hyp'Assay, a convenient cell-free assay to monitor eIF5A hypusination. Hypusination is performed in 96-well plates using recombinant human eIF5A, DHPS, and DOHH and is revealed by an antibody against hypusinated eIF5A. Pharmacological values obtained with the Hyp'Assay, such as the EC50 of DHPS for spermidine or the IC50 of GC7 for DHPS, were similar to published data, supporting the reliability of the Hyp'Assay. As a proof of concept, we synthesized four new GC7 analogs and showed, using the Hyp'Assay, that these derivatives inhibit hypusination. In summary, we present the Hyp'Assay; a reliable and sensitive assay for new hypusination inhibitors. This assay could be of interest to researchers wanting an easier way to study hypusination, and also a valuable tool for large-scale screening of chemical libraries for new hypusination inhibitors.

DOI: https://doi.org/10.1371/journal.pone.0308049

BMC Cancer. 2025 Feb 11. 25(1): 234

Multi-omics analysis reveals the impact of YAP/TEAD4-mediated EIF5A1 expression on mitochondrial apoptosis and bladder cancer progression.

Kun-Peng Li, Shun Wan, Chen-Yang Wang, Si-Yu Chen, Li Wang, Shan-Hui Liu, Li Yang.

BACKGROUND: Eukaryotic Initiation Factor 5A1 (EIF5A1) is a translation factor, and its pro-tumorigenic role has been extensively documented across various cancer types. However, its specific function in bladder cancer (BLCA) remains unclear.
METHODS: We integrated proteomics and transcriptomics data with clinical data from BLCA patients to investigate the correlation between EIF5A1 expression and BLCA, as well as its potential clinical applications. Transcriptomic data were employed to explore the downstream signaling pathways regulated by EIF5A1. Furthermore, ChIP analysis and luciferase reporter assays were conducted to identify the upstream transcription factors regulating EIF5A1.
RESULTS: EIF5A1 expression is significantly upregulated in cancer tissues and cells and is strongly associated with poor prognosis. Silencing EIF5A1 in BLCA cells significantly reduced invasiveness, and proliferative capacity. Mechanistic studies identified YAP/TEAD4 as a transcription factor that regulates EIF5A1, influencing mitochondrial-mediated apoptosis by activating the JAK2/STAT3 signaling pathway, thereby promoting BLCA progression.
CONCLUSION: Our research demonstrates that EIF5A1 is upregulated in BLCA and associated with poor prognosis. We identified TEAD4 as a potential transcriptional regulator of EIF5A1 and showed that EIF5A1 expression is associated with changes in JAK2/STAT3 signaling and mitochondrial apoptosis in BLCA.

Keywords: Bladder cancer; EIF5A1; JAK/STAT; Mitochondrial apoptosis; YAP/TEAD4

DOI: https://doi.org/10.1186/s12885-025-13522-4

Int J Mol Sci. 2025 Feb 03. pii: 1294. [Epub ahead of print]26(3):

Biological Significance and Therapeutic Promise of Programmed Ribosomal Frameshifting.

Miora Bruna Marielle Ramamonjiharisoa, Sen Liu.

Programmed Ribosomal Frameshifting (PRF) is a mechanism that alters the mRNA reading frame during translation, resulting in the production of out-of-frame proteins. PRF plays crucial roles in maintaining cellular homeostasis and contributes significantly to disease pathogenesis, particularly in viral infections. Notably, PRF can induce immune responses in the SARS-CoV-2 mRNA vaccine, further extending its biological significance. These multiple aspects of PRF highlight its potential as a therapeutic target. Since PRF efficiency can be modulated by cellular factors, its expression or silencing is context-dependent. Therefore, a deeper understanding of PRF is essential for harnessing its therapeutic potential. This review explores PRF biological significance in disease and homeostasis. Such knowledge would serve as a foundation to advance therapeutic strategies targeting PRF modulation, especially in viral infections and vaccine development.

Keywords: eIF5A; polyamine; programmed ribosomal frameshifting; translational regulation

DOI: https://doi.org/10.3390/ijms26031294

EMBO J. 2025 Feb 13.

Immediate early splicing controls translation in activated T-cells and is mediated by hnRNPC2 phosphorylation.

Mateusz Dróżdż, Luíza Zuvanov, Gopika Sasikumar, Debojit Bose, Franziska Bruening, Maria S Robles, Marco Preußner, Markus Wahl, Florian Heyd.

The fast and transient induction of immediate early genes orchestrates the cellular response to various stimuli. These stimuli trigger phosphorylation cascades that promote immediate early gene transcription independent of de novo protein synthesis. Here we show that the same phosphorylation cascades also target the splicing machinery, inducing an analogous splicing switch that we call immediate early splicing (IES). We characterize hnRNPC2-controlled IES, which depends on the MEK-ERK pathway and the T cell-specific kinase PKCθ. This splicing switch mainly targets components of the translation machinery, such as mRNAs encoding ribosomal proteins and eIF5A. Inducing the eIF5A IES protein variant is by itself sufficient to reduce global translation, and consistently, we observe reduced de novo protein synthesis early after T cell activation. We suggest that immediate early splicing and the ensuing transient decrease in translation efficiency help to coordinate the extensive changes in gene expression during T cell activation. Together, these findings set a paradigm for fast and transient alternative splicing in the immediate cellular response to activation, and provide evidence for its functional relevance during T-cell stimulation.

Keywords: Immediate Early Genes (IEG); Immediate Early Splicing (IES); PKCθ; T Cell Activation; hnRNPC

DOI: https://doi.org/10.1038/s44318-025-00374-8