Abstract
Myocarditis, inflammation of the heart muscle, affects all demographics and is a major cause of sudden and unexpected death in young people. It is most commonly caused by viral infections of the heart, with coxsackievirus B3 (CVB3) being among the most prevalent pathogens. To understand the molecular pathogenesis of CVB3 infection and provide strategies for developing treatments, we examined the role of a key nuclear pore protein 98 (NUP98) in the setting of viral myocarditis. NUP98 was cleaved as early as 2 h post-CVB3 infection. This cleavage was further verified through both the ectopic expression of viral proteases and in vitro using purified recombinant CVB3 proteases (2A and 3C), which demonstrated that CVB3 2A but not 3C is responsible for this cleavage. By immunostaining and confocal imaging, we observed that cleavage resulted in the redistribution of NUP98 to punctate structures in the cytoplasm. Targeted siRNA knockdown of NUP98 during infection further increased viral protein expression and viral titer, and reduced cell viability, suggesting a potential antiviral role of NUP98. Moreover, we discovered that expression levels of neuregulin-1 (NRG1), a cardioprotective gene, and presenilin-1 (PSEN1), a cellular protease processing the tyrosine kinase receptor ERBB4 of NRG1, were reliant upon NUP98 and were downregulated during CVB3 infection. In addition, expression of these NUP98 target genes in myocardium tissue not only occurred at an earlier phase of infection, but also appeared in areas away from the initial inflammatory regions. Collectively, CVB3-induced cleavage of NUP98 and subsequent impairment of the cardioprotective NRG1-ERBB4/PSEN1 signaling cascade may contribute to increased myocardial damage in the context of CVB3-induced myocarditis. To our knowledge, this is the first study to demonstrate the link between NUP98 and the NRG1 signaling pathway in viral myocarditis.
Highlights
Myocarditis, defined as inflammation of the myocardium, encompasses a spectrum of conditions causing considerable morbidity and mortality
To determine whether nuclear pore protein 98 (NUP98) is cleaved during coxsackievirus B3 (CVB3) infection, HeLa cells were infected with CVB3 at a multiplicity of infection (MOI) of 10 or sham-infected with phosphate-buffered saline (PBS)
These data suggest that viral protease 2A but not 3C is responsible for the cleavage of NUP98 during CVB3 infection
Summary
Myocarditis, defined as inflammation of the myocardium, encompasses a spectrum of conditions causing considerable morbidity and mortality. There are considerable gaps in our knowledge relating to the molecular pathogenesis of the disease (Feldman and McNamara, 2000). Viruses are the major causal agents of infectious myocarditis (Feldman and McNamara, 2000). Coxsackievirus B3 (CVB3) is among the most prevalent cardiotropic pathogens of viral myocarditis (Yajima and Knowlton, 2009) and has been implicated in ∼20% of acute onset heart failure and DCM (Baboonian and Treasure, 1997; Baboonian et al, 1997). Treatment for myocarditis is mostly supportive and there is no widely approved specific therapy or vaccine for CVB3 (Abelmann, 1971; McManus et al, 1988; Schultheiss et al, 2011). For DCM patients, the only definitive treatment far is mechanical assist devices and/or heart transplantation
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