The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection

Yifeng Zhang, Fabien Thery, Nicholas C. Wu, Emma K. Luhmann, Olivier Dussurget, Mariko Foecke, Clara Bredow, Daniel Jiménez-Fernández, Kevin Leandro, Antje Beling, Klaus-Peter Knobeloch, Francis Impens (), Pascale Cossart () and Lilliana Radoshevich ()
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Yifeng Zhang: Department of Microbiology and Immunology, University of Iowa Carver College of Medicine
Fabien Thery: Center for Medical Biotechnology, VIB
Nicholas C. Wu: Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Emma K. Luhmann: Department of Microbiology and Immunology, University of Iowa Carver College of Medicine
Olivier Dussurget: Institut Pasteur, Unité des Interactions Bactéries-Cellules, Département de Biologie Cellulaire et Infection
Mariko Foecke: Institut Pasteur, Unité des Interactions Bactéries-Cellules, Département de Biologie Cellulaire et Infection
Clara Bredow: Charité-Universitäts medizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Biochemistry
Daniel Jiménez-Fernández: Institute of Neuropathology, Medical Faculty, University of Freiburg
Kevin Leandro: Center for Medical Biotechnology, VIB
Antje Beling: Charité-Universitäts medizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Biochemistry
Klaus-Peter Knobeloch: Institute of Neuropathology, Medical Faculty, University of Freiburg
Francis Impens: Center for Medical Biotechnology, VIB
Pascale Cossart: Institut Pasteur, Unité des Interactions Bactéries-Cellules, Département de Biologie Cellulaire et Infection
Lilliana Radoshevich: Department of Microbiology and Immunology, University of Iowa Carver College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract ISG15 is an interferon-stimulated, ubiquitin-like protein, with anti-viral and anti-bacterial activity. Here, we map the endogenous in vivo ISGylome in the liver following Listeria monocytogenes infection by combining murine models of reduced or enhanced ISGylation with quantitative proteomics. Our method identifies 930 ISG15 sites in 434 proteins and also detects changes in the host ubiquitylome. The ISGylated targets are enriched in proteins which alter cellular metabolic processes, including upstream modulators of the catabolic and antibacterial pathway of autophagy. Computational analysis of substrate structures reveals that a number of ISG15 modifications occur at catalytic sites or dimerization interfaces of enzymes. Finally, we demonstrate that animals and cells with enhanced ISGylation have increased basal and infection-induced autophagy through the modification of mTOR, WIPI2, AMBRA1, and RAB7. Taken together, these findings ascribe a role of ISGylation to temporally reprogram organismal metabolism following infection through direct modification of a subset of enzymes in the liver.

Date: 2019
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DOI: 10.1038/s41467-019-13393-x

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