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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2019.00265

Cleavage and Sub-cellular Redistribution of Nuclear Pore Protein 98 by Coxsackievirus B3 Protease 2A Impairs Cardioprotection

 Decheng Yang1*,  paul J. Hanson1, Veena Lin1, Ye Qiu1, Huifang M. Zhang1, Guangze Zhao1, Cheng Li1, Al R. Hossain1, Saheedat Suliamon1, Marli Vlok1,  Gabriel Fung1,  Eric Jan1, Bruce M. McManus1 and  David J. Granville1
  • 1University of British Columbia, Canada

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, indicating an 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 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.

Keywords: NUP98, Coxsackievirus B3, Viral protease 2A, NRG-1, Presenilin - 1, ErbB 4, Myocarditis

Received: 04 Mar 2019; Accepted: 08 Jul 2019.

Edited by:

Shelton S. Bradrick, University of Texas Medical Branch at Galveston, United States

Reviewed by:

Encarna Martinez-Salas, Severo Ochoa Molecular Biology Center (CSIC-UAM), Spain
Xin Zhao, Institute of Microbiology, Chinese Academy of Sciences, China  

Copyright: © 2019 Yang, Hanson, Lin, Qiu, Zhang, Zhao, Li, Hossain, Suliamon, Vlok, Fung, Jan, McManus and Granville. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Decheng Yang, University of British Columbia, Vancouver, Canada, decheng.yang@hli.ubc.ca