Porcine reproductive and respiratory syndrome virus induces HMGB1 secretion via activating PKC-delta to trigger inflammatory response
Porcine reproductive and respiratory syndrome virus induces HMGB1 secretion via activating PKC-delta to trigger inflammatory response
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猪繁殖与呼吸综合征病毒通过激活PKC-delta诱导HMGB1分泌引发炎症反应
DOI：
10.1016/j.virol.2018.02.021
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Yan-Jin Zhang
中科院分区：
文献类型：
--
作者：
Rong Wang;Liping Yang;Yali Zhang;Junyan Li;Liran Xu;Yueqiang Xiao;Qian Zhang;Liang Bai;Sihai Zhao;Enqi Liu;Yan-Jin Zhang
猪繁殖与呼吸综合征病毒（PRRSV）可引起感染猪的炎症性损伤。PRRSV诱导高迁移率族蛋白1（HMGB 1）的分泌，其增强炎症反应。然而，PRRSV诱导HMGB 1分泌的机制尚不清楚。我们发现PRRSV通过激活蛋白激酶C-δ（PKCδ）诱导HMGB 1的分泌。HMGB 1的分泌与PKCδ的激活呈剂量和时间依赖性。抑制剂和siRNA抑制PKCδ可显著阻断PRRSV诱导的HMGB 1转运和分泌，提示PKCδ的激活是PRRSV介导的HMGB 1分泌所必需的。此外，PRRSV感染细胞中PKCδ的敲低导致炎性细胞因子（包括IL-1 β和IL-6）的下调。此外，发现PRRSV E和pORF 5a蛋白激活PKCδ并随后分泌HMGB 1。这些结果表明，PRRSV通过E和pORF 5a激活PKCδ诱导HMGB 1分泌。这一发现提供了对PRRSV感染的炎症反应和发病机制的见解。
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.