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MERS-CoV 4b protein interferes with the NF-?B-dependent innate immune response during infection.

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


PROVIDER: S-EPMC5800688 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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