Laboratory Animal Center, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Molecular Virology Laboratory, VA-MD College of Veterinary Medicine, University of Maryland, College Park, MD, USA.
Virology. 2018 May;518:172-183. doi: 10.1016/j.virol.2018.02.021. Epub 2018 Mar 15.
Porcine reproductive and respiratory syndrome virus (PRRSV) causes inflammatory injuries in infected pigs. PRRSV induces secretion of high mobility group box 1 (HMGB1) that enhances inflammatory response. However, the mechanism of PRRSV-induced HMGB1 secretion is unknown. Here, we discovered PRRSV induced HMGB1 secretion via activating protein kinase C-delta (PKCδ). HMGB1 secretion was positively correlated with PKCδ activation in PRRSV-infected cells in a dose and time-dependent manner. Suppression of PKCδ with inhibitor and siRNA significantly blocked PRRSV-induced HMGB1 translocation and secretion, which indicates PKCδ activation is essential for the PRRSV-mediated HMGB1 secretion. In addition, PKCδ knockdown in PRRSV-infected cells led to downregulation of inflammatory cytokines, including IL-1beta and IL-6. Moreover, PRRSV E and pORF5a proteins were found to activate PKCδ and consequent HMGB1 secretion. These results demonstrate PRRSV activates PKCδ to induce HMGB1 secretion via E and pORF5a. This finding provides insights on the inflammatory response and pathogenesis of PRRSV infection.
猪繁殖与呼吸综合征病毒（PRRSV）可引起感染猪的炎症损伤。PRRSV 诱导高迁移率族蛋白 B1（HMGB1）的分泌，从而增强炎症反应。然而，PRRSV 诱导 HMGB1 分泌的机制尚不清楚。在这里，我们发现 PRRSV 通过激活蛋白激酶 C-δ（PKCδ）诱导 HMGB1 分泌。HMGB1 分泌与 PRRSV 感染细胞中 PKCδ 的激活呈剂量和时间依赖性正相关。用抑制剂和 siRNA 抑制 PKCδ 可显著阻断 PRRSV 诱导的 HMGB1 易位和分泌，表明 PKCδ 的激活对于 PRRSV 介导的 HMGB1 分泌是必需的。此外，在 PRRSV 感染的细胞中敲低 PKCδ 会导致炎症细胞因子（包括 IL-1β和 IL-6）的下调。此外，发现 PRRSV E 和 pORF5a 蛋白可激活 PKCδ 并继而诱导 HMGB1 分泌。这些结果表明 PRRSV 通过 E 和 pORF5a 激活 PKCδ 诱导 HMGB1 分泌。这一发现为 PRRSV 感染的炎症反应和发病机制提供了新的认识。
