Abstract
Coronaviruses (CoVs) are a group of related enveloped RNA viruses that have severe consequences in a wide variety of animals by causing respiratory, enteric or systemic diseases. Porcine epidemic diarrhea virus (PEDV) is an economically important CoV distributed worldwide that causes diarrhea in pigs. nsp14 is a nonstructural protein of PEDV that is involved in regulation of innate immunity and viral replication. However, the function and mechanism by which nsp14 modulates and manipulates host immune responses remain largely unknown. Here, we report that PEDV nsp14 is an NF-κB pathway antagonist. Overexpression PEDV nsp14 protein remarkably decreases SeV-, poly (I:C)- and TNF-α-induced NF-κB activation. Meanwhile, expression of proinflammatory cytokines is suppressed by nsp14. nsp14 inhibits the phosphorylation of IKKs by interacting with IKKs and p65. Furthermore, nsp14 suppresses TNF-α-induced phosphorylation and nuclear import of p65. Overexpression nsp14 considerably increases PEDV replication. These results suggest a novel mechanism employed by PEDV to suppress the host antiviral response, providing insights that can guide the development of antivirals against CoVs.
Highlights
Coronaviruses (CoVs) are a group of related enveloped RNA viruses within the family of Coronaviridae in the order of Nidovirales that consist of four genera, Alphacoronavirus, Betacoronavirus, Deltacoronavirus and Gammacoronavirus (Gorbalenya et al 2004; Woo et al 2012)
To evaluate the effect of porcine epidemic diarrhea virus (PEDV) nsp14 on NF-κB activation, a dual luciferase reporter assay was performed to determine the antagonistic effect of nsp14 on NF-κB promoter activation induced by Sendai virus (SeV)
Overexpression nsp14 suppressed activation of NF-κB promoter in porcine intestinal epithelial cells (IPEC-J2 cell line) (Fig. 1C). These data suggest that nsp14 is an important antagonistic factor of PEDV to inhibit NF-κB activation
Summary
Coronaviruses (CoVs) are a group of related enveloped RNA viruses within the family of Coronaviridae in the order of Nidovirales that consist of four genera, Alphacoronavirus, Betacoronavirus, Deltacoronavirus and Gammacoronavirus (Gorbalenya et al 2004; Woo et al 2012). CoVs have severe health consequences by causing respiratory, enteric or systemic diseases in various animals. Two large open reading frames (ORFs), ORF1a and ORF1b, compose of major part of the viral genome and encode two large replicase polyproteins (pp1a and pp1ab), which are subsequently cleaved by viral proteases into 16 nonstructural proteins (nsps) (Ziebuhr et al 2000). These nsps, together with other viral proteins and cellular factors, assemble into a large replication-
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