Li Siwen, Wang Yu, Zhao Hongjing, Shao Yizhi, Liu Juanjuan, Xing Mingwei
Department of Physiology, College of Wildlife Resources, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
Department of Physiology, College of Wildlife Resources, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
Dev Comp Immunol. 2019 Jan;90:29-40. doi: 10.1016/j.dci.2018.08.017. Epub 2018 Aug 28.
The regulation of interferon-α signaling pathways is essential to protect the host from infection with a broad range of viruses. However, information regarding antiviral response and the specific molecular mechanism of Columba livia interferon-α (CoIFN-α) has not been reported to date. In this study, we cloned a 723bp complete ORF of CoIFN-α gene. The specific antiviral activity of CoIFN-α in VSV (TCID = 10/100 μL)-infected CEFs reached 5.5 × 10 U/mg. Moreover, our result indicated that the anti-VSV efficient of CoIFN-α might depend on the expression of NF-κB. CoIFN-α also showed high sensitivity to trypsin and relatively stable after acid, alkali or heat treatment. Moreover, CoIFN-α activated STAT/Jak signaling and autophagy to inhibit VSV-induced apoptosis. Although the expression of p53 was further increased, apoptosis was not involved in CoIFN-α against VSV. Notably, although STAT signaling was efficiently activated, knockdown p53 did inhibit the antiviral activity of the CoIFN-α via decreasing the expression of Mx1 but not weakened Jak phosphorylation. Moreover, VSV aggravated the apoptosis and the expression of cleaved Mdm2 in knockdown p53 under preincubated CoIFN-α. Taken together, p53 might as a highly interconnected regulator in IFN-α antiviral response and cleaved Mdm2 might as a dominant-negative regulator by competing with full length Mdm2 for p53 binding in virus infection. Overall, our research not only enriches CoIFN-α antiviral features but also helps explain that p53 enhance the CoIFN-α antiviral response against pigeon viral diseases.
干扰素-α信号通路的调控对于保护宿主免受多种病毒感染至关重要。然而，迄今为止，关于鸽干扰素-α（CoIFN-α）的抗病毒反应及具体分子机制的信息尚未见报道。在本研究中，我们克隆了CoIFN-α基因723bp的完整开放阅读框。CoIFN-α在感染水疱性口炎病毒（VSV，TCID = 10/100 μL）的鸡胚成纤维细胞中的特异性抗病毒活性达到5.5 × 10 U/mg。此外，我们的结果表明CoIFN-α的抗VSV效力可能依赖于NF-κB的表达。CoIFN-α对胰蛋白酶也表现出高敏感性，在酸、碱或热处理后相对稳定。此外，CoIFN-α激活STAT/Jak信号通路和自噬以抑制VSV诱导的细胞凋亡。虽然p53的表达进一步增加，但细胞凋亡不参与CoIFN-α抗VSV的过程。值得注意的是，虽然STAT信号通路被有效激活，但敲低p53确实通过降低Mx1的表达而抑制了CoIFN-α的抗病毒活性，而没有减弱Jak磷酸化。此外，在预孵育CoIFN-α的情况下，VSV加重了敲低p53细胞中的细胞凋亡和裂解型Mdm2的表达。综上所述，p53可能是干扰素-α抗病毒反应中高度相互关联的调节因子，而裂解型Mdm2可能通过在病毒感染中与全长Mdm2竞争结合p53而作为显性负调节因子。总体而言，我们的研究不仅丰富了CoIFN-α的抗病毒特性，也有助于解释p53增强CoIFN-α对鸽病毒性疾病的抗病毒反应。
