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.