Biological Relevance and Therapeutic Potential of the Hypusine Modification System

• DOI: 10.1074/jbc.m115.664490
• Publication Date: 2015-06-03T15:37:38Z
• Authors: Nora Pällmann; Melanie Braig; Henning Sievert; Michael Preukschas; Irm Hermans-Borgm...; Michaela Schweizer; Claus Henning Nagel; Melanie Neumann; Peter Wild; Eugenia Haralambieva; Christian Hagel; Carsten Bokemeyer; Joachim Hauber; Stefan Balabanov
• Keywords: Mice, Knockout; Oxidoreductases Acting on CH-NH Group Donors; 0303 health sciences; 1303 Biochemistry; Lysine; 610 Medicine & health; Mixed Function Oxygenases; 3. Good health; 1307 Cell Biology; Mice; 03 medical and health sciences; Peptide Initiation Factors; 10049 Institute of Pathology and Molecular Pathology; Neoplasms; Protein Biosynthesis; 10032 Clinic for Oncology and Hematology; 1312 Molecular Biology; Animals; Homeostasis; Humans; Protein Interaction Maps; Protein Processing, Post-Translational

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.