Biological Relevance and Therapeutic Potential of the Hypusine Modification System.

The Journal of biological chemistry 2015 Jul 24

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Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections, and inflammation. Although its contribution in translational regulation of proline repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with haploinsufficiency. Network-based bioinformatic analysis of proline repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine-modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide the first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

Nora Pällmann, Melanie Braig, Henning Sievert, Michael Preukschas, Irm Hermans-Borgmeyer, Michaela Schweizer, Claus Henning Nagel, Melanie Neumann, Peter Wild, Eugenia Haralambieva, Christian Hagel, Carsten Bokemeyer, Joachim Hauber, Stefan Balabanov. Biological Relevance and Therapeutic Potential of the Hypusine Modification System. The Journal of biological chemistry. 2015 Jul 24;290(30):18343-60