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-κB dependent response during infection. In wild-type virus infected cells， 4b localized to the nucleus， while NF-κB was retain... More
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-κB dependent response during infection. In wild-type virus infected cells， 4b localized to the nucleus， while NF-κB 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-κB was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-κB 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 α-karyopherin proteins in an NLS-dependent manner. In particular， 4b had a strong preference for binding karyopherin-α4 (KPNA4)， which is known to translocate the NF-κB protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-κB-p65 subunit. Thereby we propose a model where 4b outcompetes NF-κB for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-κB-mediated innate immune response.
