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

• DOI: 10.1371/journal.ppat.1006838
• Publication Date: 2018-01-25T18:52:12Z
• Authors: Javier Canton; Anthony R. Fehr; Raúl Fernandez-De...; Francisco J. Guti...; Maria T. Sanchez-...; Adolfo García-Sastre; Stanley Perlman; Luis Enjuanes; Isabel Sola
• Keywords: 0301 basic medicine; 570; QH301-705.5; Immunology; 610; Microbiology; Viral Proteins; 03 medical and health sciences; Cricetinae; Virology; Genetics; Animals; Humans; Biology (General); Molecular Biology; Cells, Cultured; Immune Evasion; NF-kappa B; RC581-607; Immunity, Innate; 3. Good health; Host-Pathogen Interactions; Middle East Respiratory Syndrome Coronavirus; Parasitology; Immunologic diseases. Allergy; Coronavirus Infections; Research Article

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.