Spike protein of SARS-CoV stimulates cyclooxygenase-2 expression via both calcium-dependent and calciumindependent protein kinase C pathways
Spike protein of SARS-CoV stimulates cyclooxygenase-2 expression via both calcium-dependent and calciumindependent protein kinase C pathways
复制标题
DOI：
10.1096/fj.06-6589com
复制
发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
--
作者：
Liu, Mo;Yang, Yongbo;Zhu, Ying
我们先前已经证明SARS相关冠状病毒（SARS-CoV）的核衣壳蛋白激活了环氧合酶-2（考克斯-2）的表达（1）。在本研究中，我们从SARS-CoV基因组中筛选出了另一种病毒蛋白，SARS-CoV的刺突蛋白，它在病毒刺激的考克斯-2表达中起重要作用。我们发现，上游的钙依赖性PKC同工酶PKC α，调节下游的ERK/NF-κ B B途径通过细胞外Ca 2+的流入是由SARS冠状病毒的刺突蛋白诱导。ERK/NF-κ B参与了考克斯-2启动子的激活和考克斯-2蛋白的产生。我们还证实了另一条不寻常的途径，钙非依赖性PI 3 K/PKC β/JNK/CREB途径，在刺突蛋白刺激下与钙依赖性途径协同作用诱导考克斯-2表达。该途径可被PKC ε特异性、小干扰RNA、PI 3 K/JNK激酶特异性抑制剂以及显性负性JNK阻断。PKC ε特异性siRNA也减弱了JNK的磷酸化。我们的研究结果为进一步了解SRAS-CoV刺突蛋白在SARS发病机制中的作用提供了依据。
We have previously shown that the nucleocapsid protein of SARS-associated coronavirus (SARS-CoV) activated cyclooxygenase-2 (COX-2) expression ( 1). In this study, we identified another viral protein, the spike of SARS-CoV, which played an important role in virus-stimulated COX-2 expression after screening all genes from the SARS-CoV genome. We found that an upstream calcium-dependent PKC isozyme PKC alpha that modulates the downstream ERK/ NF-kappa B pathway through an influx of extracellular Ca2+ is induced by the spike protein of SARS-CoV. The ERK/NF-kappa B was identified to be involved in the activation of COX-2 promoter and production of COX-2 protein in HEK293T cells. We also demonstrated that another unusual pathway, the calcium-independent PI3K/PKC epsilon/JNK/CREB pathway, functioned in cooperation with the calcium-dependent pathway to induce COX-2 expression upon stimulation by spike protein. This pathway can be blocked by PKC epsilon-specific, small interfering RNA, PI3K/JNK kinase-specific inhibitors as well as dominant negative JNK. PKC epsilon-specific siRNA also attenuated the phosphorylation of JNK. Our results provide evidence that helps us understand the function of SRAS-CoV spike protein in SARS pathogenesis.