title: Biological Relevance and Therapeutic Potential of the Hypusine Modification System.
abstract: 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.
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Pällmann
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, the Division of Hematology and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Braig
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center.
authors.forename: Henning
authors.initials: H
authors.lastname: Sievert
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, the Department of Molecular Pathology, Institute for Hematopathology, 22547 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Preukschas
authors.affiliation: Center for Molecular Neurobiology, and.
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.affiliation: Center for Molecular Neurobiology, and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Claus Henning
authors.initials: CH
authors.lastname: Nagel
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Haralambieva
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.affiliation: From the Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, the Division of Hematology and stefan.balabanov@usz.ch.
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
mesh_terms: D000818:Animals; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational
chemical_list: D010448:Peptide Initiation Factors; C425967:eIF-5A2; C100028:hypusine; D006899:Mixed Function Oxygenases; C047991:deoxyhypusine hydroxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase; D008239:Lysine
keywords: cancer therapy; eukaryotic initiation factor 5A (eIF5A); mouse genetics; post-translational modification (PTM); translation elongation factor