Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release
Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release
复制标题
乙酰肝素酶上调有助于猪繁殖和呼吸综合征病毒释放
DOI：
10.1128/jvi.00625-17
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发表时间：
2017-08-01
影响因子：
5.4
通讯作者：
Liu, Xiaohong
中科院分区：
文献类型：
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作者：
Guo, Chunhe;Zhu, Zhenbang;Liu, Xiaohong
猪繁殖与呼吸综合征病毒（PRRSV）持续给全球养猪业造成巨大的经济损失。硫酸乙酰肝素（HS）被PRRSV用于靶细胞的初始附着。然而，HS在PRRSV感染后期的作用以及病毒从宿主细胞释放的机制在很大程度上仍不清楚。在这项研究中，我们发现PRRSV感染导致HS表达降低，并上调肝素酶，这是唯一已知能够降解HS的酶。我们随后证实了NF-κB信号通路和组织蛋白酶L蛋白酶参与了PRRSV感染诱导的肝素酶的调控。此外，我们发现，使用小干扰RNA双链抑制肝素酶的表达增加了HS的细胞表面表达，抑制了PRRSV的复制和释放，而过表达肝素酶则降低了HS表面表达，增强了PRRSV的复制和释放。这些数据表明，PRRSV激活NF-κB和组织蛋白酶L上调和加工肝素酶，然后活性肝素酶裂解HS，导致病毒释放。我们的发现为PRRSV从宿主细胞输出的分子机制提供了新的见解，这可能有助于我们进一步了解PRRSV的发病机制。猪繁殖与呼吸综合征病毒（PRRSV）每年给世界范围内的养猪业造成巨大的经济损失。PRRSV从宿主细胞释放的分子机制在很大程度上仍然是一个谜。本研究证明，PRRSV激活NF-κB和组织蛋白酶L，上调加工肝素酶，活性肝素酶被释放到细胞外空间，发挥酶活性裂解硫酸肝素，导致病毒释放。我们的发现为PRRSV从宿主细胞输出的分子机制提供了新的见解，这可能有助于我们进一步了解PRRSV的发病机制。
ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-κB signaling pathway and cathepsin L protease were involved in regulation of PRRSV infection-induced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-κB and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-κB and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.