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Cell Metab. 2019 Aug 6;30(2):352-363.e8. doi: 10.1016/j.cmet.2019.05.003. Epub 2019 May 23.

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation.

Author information

1
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.
2
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
3
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg 79104, Germany.
4
Department of Animal Physiology and Immunology, Technical University of Munich, Freising, Germany.
5
Division of Haematology, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland.
6
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
7
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Center for Pediatrics, and Faculty of Medicine, Medical Center - University of Freiburg, Freiburg 79106, Germany.
8
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Faculty of Biology, University of Freiburg, Freiburg 79104, Germany.
9
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany. Electronic address: pearce@ie-freiburg.mpg.de.

Abstract

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.

KEYWORDS:

deoxyhypusine hydroxylase; deoxyhypusine synthase; eIF5A; hypusination; immunometabolism; macrophage activation; metabolism; polyamines

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