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Title

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

AuthorsCantón, Javier ; Fehr, Anthony R.; Fernandez-Delgado, Raúl ; Gutierrez-Alvarez, Francisco J. ; Sánchez-Aparicio, María T.; García-Sastre, Adolfo; Perlman, Stanley; Enjuanes Sánchez, Luis ; Solá Gurpegui, Isabel
Issue Date25-Jan-2018
PublisherPublic Library of Science
CitationPLoS Pathogens 14(1): e1006838 (2018)
AbstractMiddle 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.
Publisher version (URL)http://dx.doi.org/10.1371/journal.ppat.1006838
URIhttp://hdl.handle.net/10261/204524
Identifiersdoi: 10.1371/journal.ppat.1006838
e-issn: 1553-7374
issn: 553-7366
Appears in Collections:(VICYT) Colección Especial COVID-19
(CNB) Artículos
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