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MERS-CoV 4b Protein Interferes With the NF-κB-dependent Innate Immune Response During Infection

MERS-CoV 4b Protein Interferes With the NF-κB-dependent Innate Immune Response During Infection

Javier Canton, Anthony R Fehr, Raúl Fernandez-Delgado, Francisco J Gutierrez-Alvarez, Maria T Sanchez-Aparicio, Adolfo García-Sastre, Stanley Perlman, Luis Enjuanes, Isabel Sola

PLoS Pathog. 2018 Jan 25;14(1):e1006838.

PMID: 29370303

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-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LPLC81201	4-Aminophenyl-β-D-thiogalactopyranoside-Agarose 4B			Price

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