%0 Journal Article
%T MERS-CoV 4b protein interferes with the NF-百B-dependent innate immune response during infection
%A Adolfo Garc赤a-Sastre
%A Anthony R. Fehr
%A Francisco J. Gutierrez-Alvarez
%A Isabel Sola
%A Javier Canton
%A Luis Enjuanes
%A Maria T. Sanchez-Aparicio
%A Ra迆l Fernandez-Delgado
%A Stanley Perlman
%J -
%D 2018
%R 10.1371/journal.ppat.1006838
%X Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-百B dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-百B was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-百B was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-百B repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with 汐-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-汐4 (KPNA4), which is known to translocate the NF-百B protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-百B-p65 subunit. Thereby we propose a model where 4b outcompetes NF-百B for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-百B-mediated innate immune response
%K Coronaviruses
%K Transcription factors
%K Nuclear import
%K Antibodies
%K Cytokines
%K Immune response
%K Respiratory infections
%K Immunoprecipitation
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006838