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ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection

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Item Type:Article
Title:ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection
Creators Name:Bredow, C. and Thery, F. and Wirth, E.K. and Ochs, S. and Kespohl, M. and Kleinau, G. and Kelm, N. and Gimber, N. and Schmoranzer, J. and Voss, M. and Klingel, K. and Spranger, J. and Renko, K. and Ralser, M. and Mülleder, M. and Heuser, A. and Knobeloch, K.P. and Scheerer, P. and Kirwan, J. and Brüning, U. and Berndt, N. and Impens, F. and Beling, A.
Abstract:AIMS: Virus infection triggers inflammation and, may impose nutrient shortage to the heart. Supported by type I interferon (IFN) signaling, cardiomyocytes counteract infection by various effector processes, with the IFN-stimulated gene of 15 kDa (ISG15) system being intensively regulated and protein modification with ISG15 protecting mice Coxsackievirus B3 (CVB3) infection. The underlying molecular aspects how the ISG15 system affects the functional properties of respective protein substrates in the heart are unknown. METHODS AND RESULTS: Based on the protective properties due to protein ISGylation, we set out a study investigating CVB3-infected mice in depth and found cardiac atrophy with lower cardiac output in ISG15-/- mice. By mass spectrometry, we identified the protein targets of the ISG15 conjugation machinery in heart tissue and explored how ISGylation affects their function. The cardiac ISGylome showed a strong enrichment of ISGylation substrates within glycolytic metabolic processes. Two control enzymes of the glycolytic pathway, hexokinase 2 (HK2) and phosphofructokinase muscle form (PFK1), were identified as bona fide ISGylation targets during infection. In an integrative approach complemented with enzymatic functional testing and structural modeling, we demonstrate that protein ISGylation obstructs the activity of HK2 and PFK1. Seahorse-based investigation of glycolysis in cardiomyocytes revealed that, by conjugating proteins, the ISG15 system prevents the infection-/IFN-induced upregulation of glycolysis. We complemented our analysis with proteomics-based advanced computational modeling of cardiac energy metabolism. Our calculations revealed an ISG15-dependent preservation of the metabolic capacity in cardiac tissue during CVB3 infection. Functional profiling of mitochondrial respiration in cardiomyocytes and mouse heart tissue by Seahorse technology showed an enhanced oxidative activity in cells with a competent ISG15 system. CONCLUSIONS: Our study demonstrates that ISG15 controls critical nodes in cardiac metabolism. ISG15 reduces the glucose demand, supports higher ATP production capacity in the heart, despite nutrient shortage in infection, and counteracts cardiac atrophy and dysfunction.
Keywords:Metabolism, ISG15, ISGylation, Virus Infection, Glycolysis, Mitochondrial Function, Animals, Mice
Source:Cardiovascular Research
Page Range:644-657
Date:6 April 2024
Official Publication:https://doi.org/10.1093/cvr/cvae026
PubMed:View item in PubMed

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