Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells
Porcine Hemagglutinating Encephalomyelitis Virus Activation of the Integrin α5β1-FAK-Cofilin Pathway Causes Cytoskeletal Rearrangement To Promote Its Invasion of N2a Cells
复制标题
猪血凝性脑脊髓炎病毒激活整合素α5β1-FAK-Cofilin通路引起细胞骨架重排促进其侵袭N2a细胞
DOI：
10.1128/jvi.01736-18
复制
发表时间：
2019-03-01
影响因子：
5.4
通讯作者：
He, Wenqi
中科院分区：
文献类型：
--
作者：
Lv, Xiaoling;Li, Zi;He, Wenqi
猪血凝性脑脊髓炎病毒（PHEV）是一种高度嗜神经性病毒，可引起弥漫性神经元感染，造成神经损伤和高死亡率。病毒诱导的细胞骨架动力学被认为与此类神经损伤密切相关。目前，PHEV进入宿主细胞时肌动蛋白细胞骨架的调控模式及其分子机制仍不清楚。在这里，我们证明 PHEV 进入 N2a 细胞会诱导肌动蛋白细胞骨架的双相重塑和丝切蛋白活性的动态变化。病毒进入会受到肌动蛋白动力学破坏或丝切蛋白活性改变的影响。 PHEV 与整合素 α 5 β 1 结合，然后启动整合素 α 5 β 1-FAK 信号通路，导致病毒诱导的早期丝切蛋白磷酸化和 F 肌动蛋白聚合。此外，Ras 相关的 C3 肉毒杆菌毒素底物 1 (Rac1)、细胞分裂周期 42 (Cdc42) 和下游调节基因 p21 激活蛋白激酶 (PAK) 被招募为 PHEV 诱导的丝切蛋白活性途径动态变化的下游介质。总之，我们证明PHEV利用整合素α5β1-FAK-Rac1/Cdc42-PAK-LIMK-cofilin通路引起肌动蛋白细胞骨架重排来促进其自身侵袭，为PHEV致病机制和新的抗病毒靶点的开发提供理论支持。重要性PHEV是冠状病毒科的一员，是一种典型的嗜神经病毒，主要影响仔猪的神经系统产生典型的神经症状。然而，病毒引起神经损伤的机制尚未完全阐明。肌动蛋白是真核细胞细胞骨架的重要组成部分，是病原体进入宿主细胞的第一道障碍。此外，神经细胞的形态结构和功能取决于肌动蛋白骨架的动态调节。因此，从肌动蛋白细胞骨架的角度探讨PHEV引起神经元损伤的机制，不仅有助于阐明PHEV的发病机制，也为寻找新的抗病毒靶点提供理论依据。这是第一份定义细胞骨架通路信号变化与 PHEV 侵入神经细胞机制之间机制联系的报告。
Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic virus that causes diffuse neuronal infection with neurological damage and high mortality. Virus-induced cytoskeletal dynamics are thought to be closely related to this type of nerve damage. Currently, the regulation pattern of the actin cytoskeleton and its molecular mechanism remain unclear when PHEV enters the host cells. Here, we demonstrate that entry of PHEV into N2a cells induces a biphasic remodeling of the actin cytoskeleton and a dynamic change in cofilin activity. Viral entry is affected by the disruption of actin kinetics or alteration of cofilin activity. PHEV binds to integrin alpha 5 beta 1 and then initiates the integrin alpha 5 beta 1-FAK signaling pathway, leading to virus-induced early cofilin phosphorylation and F-actin polymerization. Additionally, Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division cycle 42 (Cdc42), and downstream regulatory gene p21-activated protein kinases (PAKs) are recruited as downstream mediators of PHEV-induced dynamic changes of the cofilin activity pathway. In conclusion, we demonstrate that PHEV utilizes the integrin alpha 5 beta 1-FAK-Rac1/Cdc42-PAK-LIMK-cofilin pathway to cause an actin cytoskeletal rearrangement to promote its own invasion, providing theoretical support for the development of PHEV pathogenic mechanisms and new antiviral targets.IMPORTANCE PHEV, a member of the Coronaviridae family, is a typical neurotropic virus that primarily affects the nervous system of piglets to produce typical neurological symptoms. However, the mechanism of nerve damage caused by the virus has not been fully elucidated. Actin is an important component of the cytoskeleton of eukaryotic cells and serves as the first obstacle to the entry of pathogens into host cells. Additionally, the morphological structure and function of nerve cells depend on the dynamic regulation of the actin skeleton. Therefore, exploring the mechanism of neuronal injury induced by PHEV from the perspective of the actin cytoskeleton not only helps elucidate the pathogenesis of PHEV but also provides a theoretical basis for the search for new antiviral targets. This is the first report to define a mechanistic link between alterations in signaling from cytoskeleton pathways and the mechanism of PHEV invading nerve cells.