Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Coxsackievirus Infections
/ genetics
Cytokines
/ genetics
Enterovirus B, Human
/ metabolism
Female
Gluconeogenesis
Intracellular Signaling Peptides and Proteins
/ genetics
Liver
/ metabolism
Mice
Mice, Knockout
Protein Processing, Post-Translational
RNA-Binding Proteins
/ genetics
Ubiquitin Thiolesterase
/ genetics
Ubiquitins
/ genetics
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
21
05
2019
accepted:
13
12
2019
entrez:
21
3
2020
pubmed:
21
3
2020
medline:
13
11
2020
Statut:
epublish
Résumé
Protein modification with ISG15 (ISGylation) represents a major type I IFN-induced antimicrobial system. Common mechanisms of action and species-specific aspects of ISGylation, however, are still ill defined and controversial. We used a multiphasic coxsackievirus B3 (CV) infection model with a first wave resulting in hepatic injury of the liver, followed by a second wave culminating in cardiac damage. This study shows that ISGylation sets nonhematopoietic cells into a resistant state, being indispensable for CV control, which is accomplished by synergistic activity of ISG15 on antiviral IFIT1/3 proteins. Concurrent with altered energy demands, ISG15 also adapts liver metabolism during infection. Shotgun proteomics, in combination with metabolic network modeling, revealed that ISG15 increases the oxidative capacity and promotes gluconeogenesis in liver cells. Cells lacking the activity of the ISG15-specific protease USP18 exhibit increased resistance to clinically relevant CV strains, therefore suggesting that stabilizing ISGylation by inhibiting USP18 could be exploited for CV-associated human pathologies.
Identifiants
pubmed: 32195343
doi: 10.1126/sciadv.aay1109
pii: aay1109
pmc: PMC7065878
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cytokines
0
G1p2 protein, mouse
0
Ifit1 protein, mouse
0
Ifit3 protein, mouse
0
Intracellular Signaling Peptides and Proteins
0
RNA-Binding Proteins
0
Ubiquitins
0
Usp18 protein, mouse
EC 3.4.19.-
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eaay1109Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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