TY - JOUR
T1 - The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection
AU - Zhang, Yifeng
AU - Thery, Fabien
AU - Wu, Nicholas C.
AU - Luhmann, Emma K.
AU - Dussurget, Olivier
AU - Foecke, Mariko
AU - Bredow, Clara
AU - Jiménez-Fernández, Daniel
AU - Leandro, Kevin
AU - Beling, Antje
AU - Knobeloch, Klaus Peter
AU - Impens, Francis
AU - Cossart, Pascale
AU - Radoshevich, Lilliana
N1 - Funding Information:
We thank Madeleine Vessely for her critical assessment of the paper. Myc-mTOR was a gift from David Sabatini (Addgene plasmid #1861[http://n2t.net/addgene:1861], RRID: Addgene_1861). pEGFP.90 beta was a gift from Didier Picard (Addgene plasmid #108221[http://n2t.net/addgene:108221], RRID:Addgene_108221). CMV-GFP-NMHC II-A was a gift from Robert Adelstein (Addgene plasmid #11347[http://n2t.net/ addgene:11347], RRID:Addgene_11347). We thank Dr. Jayanta Debnath for generously providing reagents (pBABEpuro GFP-LC3 construct) and Drs. Chris Stipp, Mary Wilson and John Harty for helpful discussions. We thank Edith Gouin for the shipment of strains and reagents. P.C. is supported by the European Research Council (ERC) Advanced Grant BacCellEpi (670823), and the Fondation le Roch les Mousquetaires. Project grant to A.B. by the German Research Foundation: BE 6335/6-1 and from the Foundation for Experimental Biomedicine Zurich, Switzerland. C.B. was supported by International Max Planck Research School for Infectious Diseases and Immunology (IMPRS‐IDI), Berlin. P.C., A.B., K.P.K., and F.I. are supported by ERANET Infect-ERA BacVIRISG15. K.P.K. is supported by a DFG grant KN590/7-1. F.I. is supported by Odysseus grant G0F8616N from the Research Foundation Flanders (FWO). P.C. is a Senior International Research Scholar of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075610966&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075610966&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13393-x
DO - 10.1038/s41467-019-13393-x
M3 - Article
C2 - 31772204
AN - SCOPUS:85075610966
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5383
ER -