bims-hypusi 2025-01-19 papers

Issue of 2025–01–19
four papers selected by
Sebastian J. Hofer, University of Graz

Structure. 2025 Jan 09. pii: S0969-2126(24)00546-X. [Epub ahead of print]

The structural biology of deoxyhypusination complexes.

Elżbieta Wątor-Wilk, Piotr Wilk, Przemysław Grudnik.

Deoxyhypusination is the first rate-limiting step of the unique post-translational modification-hypusination-that is catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). This modification is essential for the activation of translation factor 5A in eukaryotes (eIF5A) and Archaea (aIF5A). This perspective focuses on the structural biology of deoxyhypusination complexes in eukaryotic and archaeal organisms. Based on recently published crystal and cryogenic electron microscopy (cryo-EM) structures of deoxyhypusination complexes from three different organisms, we compare the structural features and stoichiometries of DHS-IF5A complexes across different species. We discuss conserved elements in the active site architecture and binding interfaces as well as significant differences in their stoichiometry and regulation mechanisms. The structural insights provide a comprehensive understanding of the deoxyhypusination process and highlight evolutionary adaptations across the domains of life. Future research should focus on the regulatory mechanisms governing DHS activity and the functional implications of stoichiometric variations in different organisms.

Keywords: PTM; aIF5A; deoxyhypusination; deoxyhypusine synthase; eIF5A; hypusination; hypusine; translation

DOI: https://doi.org/10.1016/j.str.2024.12.011

Nat Commun. 2025 Jan 10. 16(1): 223

Girolline is a sequence context-selective modulator of eIF5A activity.

Tilman Schneider-Poetsch, Yongjun Dang, Wakana Iwasaki, Mayumi Arata, Yuichi Shichino, Ali Al Mourabit, Celine Moriou, Daniel Romo, Jun O Liu, Takuhiro Ito, Shintaro Iwasaki, Minoru Yoshida.

Natural products have a long history of providing probes into protein biosynthesis, with many of these compounds serving as therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Its precise mechanism of action, however, has remained unknown. The data we present here suggests that girolline is a sequence-selective modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling where translational progress is impeded, including on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control and in maintaining the efficiency of translational progress. Girolline helped to deepen our understanding of the interplay between protein production and quality control in a physiological setting and offers a potent chemical tool to selectively modulate gene expression.

DOI: https://doi.org/10.1038/s41467-024-54838-2

Anal Cell Pathol (Amst). 2025 ;2025 5595692

circ-ZEB1 Enhances NSCLC Metastasis and Proliferation by Modulating the miR-491-5p/EIF5A Axis.

Qi Wang, Shengying Ling, Jia Lv, Lina Wu.

Background: Circular RNAs (circRNAs), covalently closed single-stranded RNAs, have been implicated in cancer progression. A previous investigation revealed that circ-ZEB1 is expressed abnormally in liver cancer. However, the roles of circ-ZEB1 in non-small cell lung cancer (NSCLC) are unknown. Methods: In this study, we used fluorescence in situ hybridization (FISH) and RT-qPCR to study circ-ZEB1 expression in NSCLC cells and tissues. A luciferase reporter assay was performed to validate downstream targets of circ-ZEB1. Transwell migration, 5-ethynyl-20-deoxyuridine (EdU), and cell counting kit-8 (CCK8) assays were performed to assess proliferation and migration. In vivo metastasis and tumorigenesis assays were also performed to investigate circ-ZEB1 functions during NSCLC. Results: Our results showed that circ-ZEB1 expression was increased in NSCLC tissues and cells. circ-ZEB1 downregulation suppressed NSCLC cell proliferation as well as migration in vitro and in vivo. Luciferase data confirmed EIF5A and miR-491-5p as downstream targets of circ-ZEB1. EIF5A overexpression and miR-491-5p suppression reversed NSCLC cell migration post circ-ZEB1 silencing. Conclusion: Our collective findings advised that circ-ZEB1 takes part in the malignant progression through regulating the miR-491-5p/EIF5A axis, highlighting its potential as an effective NSCLC therapeutic target.

Keywords: EIF5A; circ-ZEB1; miR-491-5p; non-small cell lung cancer (NSCLC)

DOI: https://doi.org/10.1155/ancp/5595692

Bioorg Chem. 2025 Jan 07. pii: S0045-2068(25)00015-X. [Epub ahead of print]155 108135

Spermidine synthase promotes liver cancer progression in a paracrine manner by altering the macrophage immunometabolic state.

Sihang Yu, Yuanxin Zhao, Qingqing Liu, Jian Wang, Jiaying Fu, Runyuan Li, Yuan Yuan, Xiaoyu Yan, Jing Su.

PURPOSE: Understanding the molecular mechanisms of adaptive regulation in the tumor microenvironment is crucial for precision therapy in hepatocellular carcinoma (HCC). We hypothesized that cargo proteins carried by extracellular vesicles (EVs) released in a hypoxic microenvironment might promote HCC progression by remodeling tumor-associated macrophages (TAMs).
METHODS: EV protein analysis by label-free proteomics mass spectrometry of HCC cell lines of different tumor grades was performed. The promotional effect if spermidine synthase（SRM） on M2 polarized TAMs was further investigated using various biological approaches.
RESULTS: SRM expression was positively correlated with liver cancer progression in HCC cell lines, liver cancer samples, and nude mouse models. In a mouse model, SRM expression was positively correlated with TAM infiltration and liver cancer progression. Pan-cancer dataset analysis confirmed that SRM overexpression in HCC tumors is correlated with poor patient prognosis. However, a hypoxic microenvironment is an internal driving factor for exosomal SRM that participates in microenvironmental modifications. Moreover, we defined a hitherto unknown pattern of microenvironmental crosstalk involving SRM in EVs, whereby macrophages complete the phenotypic fate of M2 tumor-associated macrophages through SRM uptake.
CONCLUSION: SRM regulation within the immune microenvironment is metabolically driven. By upregulating spermidine, which serves as a substrate for eIF5A hypusination, excessive oxidative phosphorylation (OXPHOS) assembly is achieved. This, in turn, leads to the expression of immunosuppressive marker molecules and ultimately promotes liver cancer progression. SRM, which is enriched in the EVs of HCC cells under hypoxic conditions, acts as a potent regulator linking polyamine and energy metabolism in TAMs, thereby promoting liver cancer progression.

Keywords: Biomarker; Exosome; Hepatocellular carcinoma; Hypusine; Macrophage; OXPHOS; Spermidine synthase; eIF5A

DOI: https://doi.org/10.1016/j.bioorg.2025.108135