ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage.

Hannah Louise Neumaier,Shelly Harel,Karin Klingel,Ziya Kaya,Arnd Heuser,Meike Kespohl,Antje Beling

doi:10.3390/cells9051093

Abstract

Inhibition of proteasome function by small molecules is highly efficacious in cancer treatment. Other than non-selective proteasome inhibitors, immunoproteasome-specific inhibitors allow for specific targeting of the proteasome in immune cells and the profound anti-inflammatory potential of such compounds revealed implications for inflammatory scenarios. For pathogen-triggered inflammation, however, the efficacy of immunoproteasome inhibitors is controversial. In this study, we investigated how ONX 0914, an immunoproteasome-selective inhibitor, influences CoxsackievirusB3 infection in NMRI mice, resulting in the development of acute and chronic myocarditis, which is accompanied by formation of the immunoproteasome in heart tissue. In groups in which ONX 0914 treatment was initiated once viral cytotoxicity had emerged in the heart, ONX 0914 had no anti-inflammatory effect in the acute or chronic stages. ONX 0914 treatment initiated prior to infection, however, increased viral cytotoxicity in cardiomyocytes, promoting infiltration of myeloid immune cells into the heart. At this stage, ONX 0914 completely inhibited the β5 subunit of the standard cardiac proteasome and less efficiently blocked its immunoproteasome counterpart LMP7. In conclusion, ONX 0914 unselectively perturbs cardiac proteasome function in viral myocarditis of NMRI mice, reduces the capacity of the host to control the viral burden and promotes cardiac inflammation.

Highlights

The ubiquitin-proteasome system (UPS) is an integral part of cellular proteostasis, functioning as the primary route for intracellular degradation of misfolded, damaged, or short-lived proteins [1].The ubiquitin conjugation machinery marks these proteins for recognition by the proteolytic complex, the proteasome
Based on the anti-inflammatory capacity accomplished by treating mice with i-proteasome-selective inhibitors, in this study we determined how ONX 0914, a broadly studied epoxyketone-based compound with irreversible inhibitory kinetics, affects virus-induced inflammation and remodeling processes, resulting in chronic myocarditis
Using the NMRI mouse model of Coxsackievirus B3 (CVB3) myocarditis, we found that

Summary

Introduction

The ubiquitin-proteasome system (UPS) is an integral part of cellular proteostasis, functioning as the primary route for intracellular degradation of misfolded, damaged, or short-lived proteins [1].The ubiquitin conjugation machinery marks these proteins for recognition by the proteolytic complex, the proteasome. In comparison to its standard proteasome counterpart, the i-proteasome accelerates the proteolysis of specific peptide substrates [8,9] and allows for the facilitated degradation of oxidant-damaged proteins, which may accumulate during inflammation, for example [3,10,11]. While this specific adaptation of proteasome function is of particular relevance in non-immune cells with high standard proteasome abundance under basal conditions, immune cells exhibit high i-proteasome and low standard proteasome expression levels in their naive state. This cell-specific proteasome-isoform expression pattern in non-immune and immune cells initiated the structure-guided design of specific proteasome inhibitors, targeting the i-proteasome [12,13]

Methods

Results

Conclusion