Proteasomal Protein Degradation: Adaptation of Cellular Proteolysis With Impact on Virus—and Cytokine-Mediated Damage of Heart Tissue During Myocarditis

Abstract

Viral myocarditis is an inflammation of the heart muscle triggered by direct virus-induced cytolysis and immune response mechanisms with most severe consequences during early childhood. Acute and long-term manifestation of damaged heart tissue and disturbances of cardiac performance involve virus-triggered adverse activation of the immune response and both immunopathology, as well as, autoimmunity account for such immune-destructive processes. It is a matter of ongoing debate to what extent subclinical virus infection contributes to the debilitating sequela of the acute disease. In this review, we conceptualize the many functions of the proteasome in viral myocarditis and discuss the adaptation of this multi-catalytic protease complex together with its implications on the course of disease. Inhibition of proteasome function is already highly relevant as a strategy in treating various malignancies. However, cardiotoxicity and immune-related adverse effects have proven significant hurdles, representative of the target's wide-ranging functions. Thus, we further discuss the molecular details of proteasome-mediated activity of the immune response for virus-mediated inflammatory heart disease. We summarize how the spatiotemporal flexibility of the proteasome might be tackled for therapeutic purposes aiming to mitigate virus-mediated adverse activation of the immune response in the heart.

Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection

“…Since the modified proteasome activity, inherent in LMP7 −/− mice with ip dysfunction [ 10 , 12 ], apparently neutralizes the immunomodulatory potential of the ip that can be targeted in wild-type mice by inhibitors of this proteasome isoform, we questioned how other immune-related aspects with a specific functional requirement for intact ip proteolysis are influenced in LMP7 −/− mice during CV infection. The peripheral blood count in CV infected mice showed a significantly elevated level of leukocytes, and may be showing a trend towards higher neutrophil counts in LMP7 −/− mice (Fig.…”

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

“…Altogether, we conclude that alterations of the adaptive immune response, which might be mediated by ONX 0914 [30,54], are not among its main effectors, leading to exacerbated pathology in CVB3-infected NMRI mice. Quite in contrast to its pleiotropic cellular functions in the regulation of inflammatory signaling cascades and in antigen presentation in the host cell, the UPS can also be utilized to control the abundance of viral proteins in infected cells [25]. Direct interactions between viral and host-cell proteins [55] may offer a putative explanation for how inhibition of the proteasome complex, as shown here for ONX 0914 treatment in NMRI mice, might affect the viral load independent of the innate and adaptive immune responses.…”

“…Nevertheless, the availability of selective i-proteasome inhibitors paved the way towards the definition of new functions of the i-proteasome. These involve control of DAMP-or PAMP-triggered signaling responses, resulting in elevated production of cytokines, e.g., by innate myeloid cells, altered T cell activation and differentiation, B cell function, or immune cell survival [23][24][25]. Based on these multidimensional immune cellular functions, it was expected that i-proteasome inhibitors would be capable of hindering inflammation-driven carcinogenesis [26,27], autoimmune-related inflammation [20,28,29], or transplant rejection [22,30].…”

Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming

“…The biosynthesis of molecules, needed for an efficient antiviral response against CV, consumes large proportions of cellular adenosine triphosphate (ATP), and in infected cells, IFNs induce processes that activate the uptake and turnover of glucose (28). After the first viremia, when systemic IFN production gradually declines, a second viremia and replication phase of CV emerges in heart tissue, culminating in inflammatory tissue damage and cardiac dysfunction (30). In this state, IFN signaling constrains CV pathology as well (31,32).…”