Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy

Abstract

The primary intracellular protein degradation systems, including the ubiquitin-proteasome and the lysosome pathways, have been emerging as central regulators of viral infectivity, inflammation, and viral pathogenicity. Viral myocarditis is an inflammatory disease of the myocardium caused by virus infection in the heart. The disease progression of viral myocarditis occurs in three distinct stages: acute viral infection, immune cell infiltration, and cardiac remodelling. Growing evidence suggests a crucial role for host proteolytic machineries in the regulation of the pathogenesis and progression of viral myocarditis in all three stages. Cardiotropic viruses evolve different strategies to subvert host protein degradation systems to achieve successful viral replication. In addition, these proteolytic systems play important roles in the activation of innate and adaptive immune responses during viral infection. Recent evidence also suggests a key role for the ubiquitin-proteasome and lysosome systems as the primary effectors of protein quality control in the regulation of cardiac remodelling. This review summarizes the recent advances in understanding the direct interaction between cardiotropic viruses and host proteolytic systems, with an emphasis on coxsackievirus B3, one of the primary aetiological agents causing viral myocarditis, and highlights possible roles of the host degradation systems in the pathogenesis of viral myocarditis and its progression to dilated cardiomyopathy.

Figure 1

Primary intracellular protein degradation systems in eukaryotes. (A) The ubiquitin-proteasome system. The 20S proteasome is latent and present in cells in two forms, constitutive proteasome and immunoproteasome, which differ in the composition of three β-catalytic subunits. There are at least two classes of proteasome activators. The 19S (PA700) activator binds to the constitutive 20S proteasome to form the 26S (19S–20S) or 30S (19S–20S–19S) proteasome, which is primarily responsible for the degradation of ubiquitinated proteins in an ATP-dependent manner. Proteasome activator 11S (PA28) binds to either the constitutive or the immunoproteasome and facilitates ATP- and ubiquitin-independent protein degradation. In addition, 19S can also form a hybrid proteasome (19S–20S–11S) with 20S proteasome and 11S, which enhances the proteolytic efficiency of antigen processing. For ubiquitin (ub)-dependent proteolysis, substrates are first covalently attached to multiple ubiquitin moieties via the action of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) in an ATP-dependent manner. (B) The autophagy pathway. A portion of the cytoplasm including organelles is sequestrated by the autophagic isolation membrane, which results in the formation of an autophagosome. The outer membrane of the autophagosome eventually fuses with the lysosome to degrade its contents.

Figure 2

Interaction between coxsackievirus and the host proteolytic systems. (A) Following entry into the cell, the positive-strand coxsackieviral RNA directs synthesis of a polyprotein via the host translational machinery. This polyprotein is subsequently processed into individual structural (VP1–VP4) and non-structural (2A, 2B, 2C, 3A, 3B, 3C, and 3D) proteins following cleavage by viral proteases 2A and 3C. Viral RNA-dependent RNA polymerase 3D (3D^pol) then synthesizes negative-strand viral RNA intermediate which serves as a template for transcription of multiple progeny genomes. (B) Coxsackievirus infection facilitates protein ubiquitination, which subsequently increases host antiviral protein degradation (e.g. p53) by the proteasome and/or viral protein modification (e.g. viral 3D^pol) by ubiquitination. Viral protein 3A likely promotes protein ubiquitination by recruiting host ubiquitin ligases to the viral replication complex. Degradation of host anti-viral proteins and ubiquitin-mediated modification of viral protein represent strategies that CVB3 evolves to promote its infectivity. DUBs, deubiquitinating enzymes. (C) Coxsackievirus infection induces the formation of cellular autophagosome without promoting protein degradation by the lysosome, probably through the activation of eIF2α. The host double-membrane autophagosomes may serve as sites for viral RNA synthesis by recruiting the polyribosomes and assembling the viral replication complex.

Figure 3

The role of the protein degradation systems in viral myocarditis leading to dilated cardiomyopathy. Viral myocarditis consists of three stages: viral infection, immune response, and cardiac remodelling progression to dilated cardiomyopathy. (A) During the viral infection stage, virus evolves different strategies to utilize the host UPS and the autophagy machinery to facilitate its replication (see Figure 2 for the possible mechanisms). (B) At the immune response stage, virus infection induces the formation of immunoproteasome to increase MHC class I antigen presentation. Meanwhile, production of pro-inflammatory cytokines is enhanced, partially through UPS-mediated NFκB activation. Autophagy may also contribute to immune-mediated pathogenesis by modulating MHC class II antigen presentation. (C) Pathological cardiac remodelling leads to dilated cardiomyopathy. Increased accumulation of abnormal ubiquitin-protein conjugates/aggregates and elevated oxidative stress lead to the eventual impairment of UPS function, subsequently result in abnormal regulation of contractile apparatus expression and also trigger apoptosis and autophagic cell death. As a result of myocyte loss and decreased contractile property, the left ventricle of the heart begins to dilate to compensate for impaired cardiac function.