RT Journal Article
T1 The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis
A1 Jimenez-Guardeño, Jose Manuel
A1 Nieto-Torres, Jose Luis
A1 DeDiego, Marta L.
A1 Regla-Nava, Jose Angel
A1 Fernandez-Delgado, Raul
A1 Castaño-Rodriguez, Carlos
A1 Enjuanes, Luis
K1 COVID-19
K1 Coronavirus
K1 Virus
K1 Virología
AB 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.
YR 2014
FD 2014
LK https://hdl.handle.net/10630/34247
UL https://hdl.handle.net/10630/34247
LA eng
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 21 ene 2026