Abstract
Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease in pigs caused by PRRS virus (PRRSV). Although PRRSV infection-induced cell apoptosis has been established, the related viral protein is still unknown. Here, we reported that PRRSV nonstructural protein 4 (nsp4) was a critical apoptosis inducer. Nsp4 could activate caspase-3, -8, and -9. Using truncated constructs without different domains in nsp4, we demonstrated that the full-length of nsp4 structure was required for its apoptosis-inducing activity. Furthermore, using site-directed mutagenesis to inactivate the 3C-like serine protease activity of nsp4, we showed that nsp4-induced apoptosis was dependent on its serine protease activity. The ability of nsp4 to induce apoptosis was significantly impaired by His39, Asp64, and Ser118 mutations, suggesting that His39, Asp64, and Ser118 were essential for nsp4 to trigger apoptosis. In conclusion, our present work showed that PRRSV nsp4 could induce apoptosis in host cells and might be partially responsible for the apoptosis induced by PRRSV infection. PRRSV 3C-like protease-mediated apoptosis represents the first report in the genus Arterivirus, family Arteriviridae.
Highlights
Porcine reproductive and respiratory syndrome (PRRS) is an economically important disease of swine industry worldwide, which is characterized with respiratory illness in piglets and severe reproductive problems in sows and gilts [1,2]
We further demonstrated that nsp4-induced cell apoptosis was dependent on its 3C-like serine protease activity, and His39, Asp64, and Ser118 were essential for nsp4 to induce apoptosis
Evidence of apoptosis has been reported in alveolar macrophages, porcine intravascular monocytes, and lymphocytes in the lungs and lymph nodes of infected pigs, which might be responsible for the dramatic reduction in the number of these cells in PRRSVinfected pigs [19,26,27]
Summary
Porcine reproductive and respiratory syndrome (PRRS) is an economically important disease of swine industry worldwide, which is characterized with respiratory illness in piglets and severe reproductive problems in sows and gilts [1,2]. The etiologic agent, PRRS virus (PRRSV), is an enveloped single-stranded positive sense RNA virus and is classified into the genus Arterivirus, family Arteriviridae, order Nidovirales [4]. The genome is approximately 15.4 kb in length and contains 10 open reading frames (ORFs), designated as ORF1a, ORF1b, and ORFs 2-7. ORFs 2-7 encode structural proteins including GP2a, GP2b, GP3, GP4, GP5, GP5a, M, and N protein, respectively. The replicative enzymes of PRRSV are encoded in ORF1a and ORF1b, which constitute almost 75% of the genome [1]
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