bims-hypusi 2023-04-02 papers

Issue of 2023‒04‒02
three papers selected by
Sebastian J. Hofer
University of Graz

Nat Commun. 2023 Mar 27. 14(1): 1698

Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders.

Elżbieta Wątor, Piotr Wilk, Artur Biela, Michał Rawski, Krzysztof M Zak, Wieland Steinchen, Gert Bange, Sebastian Glatt, Przemysław Grudnik.

Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS), however, the molecular details of the DHS-mediated reaction remained elusive. Recently, patient-derived variants of DHS and eIF5A have been linked to rare neurodevelopmental disorders. Here, we present the cryo-EM structure of the human eIF5A-DHS complex at 2.8 Å resolution and a crystal structure of DHS trapped in the key reaction transition state. Furthermore, we show that disease-associated DHS variants influence the complex formation and hypusination efficiency. Hence, our work dissects the molecular details of the deoxyhypusine synthesis reaction and reveals how clinically-relevant mutations affect this crucial cellular process.

DOI: https://doi.org/10.1038/s41467-023-37305-2

Anticancer Res. 2023 Apr;43(4): 1437-1448

Expression of Eukaryotic Translation Initiation Factors in the Urothelial Carcinoma of the Bladder.

Jeton Luzha, Norbert Nass, Piotr Czapiewski, Nicolas Schroeder, Thomas Kalinski, Martin Schostak, Christoph Schatz, Burkhard Jandrig, Johannes Haybaeck.

BACKGROUND/AIM: Urothelial carcinoma (UC) of the urinary bladder is the second most common tumor in the field of urology and is characterized by a relatively aggressive growth behavior. New therapeutic approaches are required to improve the prognosis of affected patients. We hypothesized a link between dysregulation of eIFs and the development of UC. Therefore, in the present work, we investigated the expression behavior of eIF1, eIF1AY, eIF1AX, eIF2α, eIF3a, eIF3b, eIF4B, eIF4E, eIF4G, eIF5A, eIF5B, and eIF6 in UC compared with that in urothelial tissue.MATERIALS AND METHODS: Paraffin-embedded tumor tissue samples from 107 patients suffering from UC were examined. Seventy-six patients contained adjacent urothelial tissue. Three tumor tissue cylinders (tumor collective) and two urothelial tissue cylinders (control collective) were collected per patient and embedded in tissue microarray (TMA) blocks. Immunohistochemical staining of the TMA sections was then performed. The staining results were assessed semi-quantitatively. Staining intensities and immunoreactive scores (IRS) of both collectives were compared. In each case, a distinction was made between cytoplasmic and nuclear staining.
RESULTS: Significant up-regulation of eIF1AY, eIF2α, eIF3a, eIF3b, eIF4B, eIF4G, eIF5B, and eIF6 was found in the cytoplasm of UC. In contrast, eIF1 and eIF5A were significantly down-regulated in the cytoplasm of UC. eIF5A and eIF6 were significantly down-regulated in the nuclei of UC.
CONCLUSION: Dysregulation of eIFs in the urothelium of the urinary bladder is linked to carcinogenesis at this site.

Keywords: Translation; bladder cancer; eukaryotic initiation factors (eIFs); initiation; urothelial carcinoma

DOI: https://doi.org/10.21873/anticanres.16292

Sci Adv. 2023 Mar 29. 9(13): eade1792

mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs.

Deniz Bartsch, Kaustubh Kalamkar, Gaurav Ahuja, Jan-Wilm Lackmann, Jürgen Hescheler, Timm Weber, Hisham Bazzi, Massimiliano Clamer, Sasha Mendjan, Argyris Papantonis, Leo Kurian.

The blueprints of developing organs are preset at the early stages of embryogenesis. Transcriptional and epigenetic mechanisms are proposed to preset developmental trajectories. However, we reveal that the competence for the future cardiac fate of human embryonic stem cells (hESCs) is preset in pluripotency by a specialized mRNA translation circuit controlled by RBPMS. RBPMS is recruited to active ribosomes in hESCs to control the translation of essential factors needed for cardiac commitment program, including Wingless/Integrated (WNT) signaling. Consequently, RBPMS loss specifically and severely impedes cardiac mesoderm specification, leading to patterning and morphogenetic defects in human cardiac organoids. Mechanistically, RBPMS specializes mRNA translation, selectively via 3'UTR binding and globally by promoting translation initiation. Accordingly, RBPMS loss causes translation initiation defects highlighted by aberrant retention of the EIF3 complex and depletion of EIF5A from mRNAs, thereby abrogating ribosome recruitment. We demonstrate how future fate trajectories are programmed during embryogenesis by specialized mRNA translation.

DOI: https://doi.org/10.1126/sciadv.ade1792