The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis

A recombinant severe acute respiratory syndrome coronavirus (sars-cov) lacking the envelope (e) protein is attenuated in vivo. here we report that e protein pdz-binding motif (pbm),a domain involved in protein-protein interactions,is a major determinant of virulence. elimination of sars-cov e protein pbm by using reverse genetics caused a reduction in the deleterious exacerbation of the immune response triggered during infection with the parental virus and virus attenuation. cellular protein syntenin was identified to bind the e protein pbm during sars-cov infection by using three complementary strategies,yeast two-hybrid,reciprocal coimmunoprecipitation and confocal microscopy assays. syntenin redistributed from the nucleus to the cell cytoplasm during infection with viruses containing the e protein pbm,activating p38 mapk and leading to the overexpression of inflammatory cytokines. silencing of syntenin using sirnas led to a decrease in p38 mapk activation in sars-cov infected cells,further reinforcing their functional relationship. active p38 mapk was reduced in lungs of mice infected with sars-covs lacking e protein pbm as compared with the parental virus,leading to a decreased expression of inflammatory cytokines and to virus attenuation. interestingly,administration of a p38 mapk inhibitor led to an increase in mice survival after infection with sars-cov,confirming the relevance of this pathway in sars-cov virulence. therefore,the e protein pbm is a virulence domain that activates immunopathology most likely by using syntenin as a mediator of p38 mapk induced inflammation. © 2014 jimenez-guardeño et al.