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, Lilliana Radoshevich

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number5383
JournalNature communications
Issue number1
StatePublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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