Journal article
Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming
Science advances, Vol.6(11), pp.eaay1109-eaay1109
03/01/2020
DOI: 10.1126/sciadv.aay1109
PMCID: PMC7065878
PMID: 32195343
Abstract
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 ISG1 5specific 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.
Details
- Title: Subtitle
- Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming
- Creators
- Meike Kespohl - Berlin Institute of Health at Charité - Universitätsmedizin BerlinClara Bredow - Berlin Institute of Health at Charité - Universitätsmedizin BerlinKarin Klingel - University of TübingenMartin Voss - Charite Univ Med Berlin, Berlin, GermanyAnna Paeschke - Berlin Institute of Health at Charité - Universitätsmedizin BerlinMartin Zickler - Berlin Institute of Health at Charité - Universitätsmedizin BerlinWolfgang Poller - Humboldt-Universität zu BerlinZiya Kaya - University Hospital HeidelbergJohannes Eckstein - Berlin Institute of Health at Charité - Universitätsmedizin BerlinHenry Fechner - Technische Universität BerlinJoachim Spranger - Humboldt-Universität zu BerlinMichael Faehling - Charite Univ Med Berlin, Berlin, GermanyEva Katrin Wirth - Humboldt-Universität zu BerlinLilliana Radoshevich - University of IowaFabien Thery - Ghent University HospitalFrancis Impens - Ghent University HospitalNikolaus Berndt - Berlin Institute of Health at Charité - Universitätsmedizin BerlinKlaus-Peter Knobeloch - University of FreiburgAntje Beling - Berlin Institute of Health at Charité - Universitätsmedizin Berlin
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.6(11), pp.eaay1109-eaay1109
- Publisher
- Amer Assoc Advancement Science
- DOI
- 10.1126/sciadv.aay1109
- PMID
- 32195343
- PMCID
- PMC7065878
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Number of pages
- 19
- Grant note
- Federal Ministry for Education and Research (ERAinfect, BacVirISG15) Infect-ERA BacVIRISG15 G0F8616N / Odysseus from Research Foundation Flanders (FWO); FWO Federal Ministry for Education and Research; Federal Ministry of Education & Research (BMBF) Foundation for Experimental Biomedicine (Zurich, Switzerland) International Max Planck Research School for Infectious Diseases and Immunology (IMPRS-IDI), Berlin KN490/7-1 / DFG; German Research Foundation (DFG); European Commission Hengstberger research fellowship 31L0057 / German Systems Biology Programs "LiSyM" - Federal Ministry of Education and Research BE 6335/5-1; 6335/6-1; KN 590/7-1 / German Research Foundation; German Research Foundation (DFG)
- Language
- English
- Date published
- 03/01/2020
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology
- Record Identifier
- 9984297330002771
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