Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis
Open Access
- 1 September 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 7 (9), e1002233
- https://doi.org/10.1371/journal.ppat.1002233
Abstract
Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu. The proteasome recognizes and degrades protein substrates tagged with poly-ubiquitin chains. Immune cells and cells activated by inflammatory cytokines/interferons express immunoproteasomes (IPs) that are characterized by unique catalytic subunits with increased substrate turnover. In infectious disease, the function of IPs is still a matter of controversial debate. Here, we report on a novel innate function of IPs in viral infection. We studied the murine model of acute enterovirus myocarditis, which represents one of the most common viral disease entities among young people. We found that IPs protect the pathogen-challenged tissue from severe injury, which was reflected in severe myocardial destruction and large inflammatory foci in mice lacking IPs. We show data that this prevention of excessive inflammatory tissue damage in viral heart disease is primarily attributed to preservation of protein homeostasis due to accelerated substrate turnover by IPs. Thus, a major innate function of IPs in viral infection is to stabilize cell viability in inflammatory tissue injury.Keywords
This publication has 51 references indexed in Scilit:
- Aging and Immune Function: Molecular Mechanisms to InterventionsAntioxidants and Redox Signaling, 2011
- NF-κB in the regulation of epithelial homeostasis and inflammationCell Research, 2010
- Unexpected Role for the Immunoproteasome Subunit LMP2 in Antiviral Humoral and Innate Immune ResponsesPublished by The American Association of Immunologists ,2010
- Sent to DestroyCirculation Research, 2010
- DAMPening Inflammation by Modulating TLR SignallingMediators of Inflammation, 2010
- Differential Interferon Responses Enhance Viral Epitope Generation by Myocardial Immunoproteasomes in Murine Enterovirus MyocarditisThe American Journal of Pathology, 2009
- Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 DisordersThe American Journal of Pathology, 2006
- Proteasome-mediated degradation of IκBα and processing of p105 in Crohn disease and ulcerative colitisJCI Insight, 2006
- Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infectionJCI Insight, 2006
- Structure of 20S proteasome from yeast at 2.4Å resolutionNature, 1997