The Capsid Protein VP1 of Coxsackievirus B Induces Cell Cycle Arrest by Up-Regulating Heat Shock Protein 70
The Capsid Protein VP1 of Coxsackievirus B Induces Cell Cycle Arrest by Up-Regulating Heat Shock Protein 70
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柯萨奇病毒 B 的衣壳蛋白 VP1 通过上调热休克蛋白 70 诱导细胞周期停滞
DOI：
10.3389/fmicb.2019.01633
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发表时间：
2019
影响因子：
5.2
通讯作者：
Zhao Wenran
中科院分区：
文献类型：
--
作者：
Wang Yao;Zhao Shuoxuan;Chen Yang;Wang Tianying;Dong Chaorun;Wo Xiaoman;Zhang Jian;Dong Yanyan;Xu Weizhen;Feng Xiaofeng;Qu Cong;Wang Yan;Zhong Zhaohua;Zhao Wenran
操纵细胞周期是病毒产生有利细胞环境以促进病毒复制的常用策略之一。柯萨奇病毒B （CVB）是引起人类心肌炎和心肌病的主要病毒病原体之一。由于其基因组小，CVB依赖于细胞机制进行高效复制。然而，CVB的结构和非结构成分如何操纵细胞周期尚不清楚。在这项研究中，我们证明了CVB3型（CVB3）的衣壳蛋白VP1诱导细胞周期阻滞在G1期。G1阻滞是cyclin E水平降低和p27Kip1积累的结果。对表达VP1细胞基因表达谱的研究表明，热休克蛋白70-1 （Hsp70-1）和Hsp70-2的表达均显著上调。敲低Hsp70导致cyclin E水平升高，p27Kip1水平降低。我们进一步证明，在表达VP1的细胞中，直接促进Hsp70表达的热休克因子1的磷酸化也增加了。此外，我们发现CVB3感染也诱导G1阻滞，可能是由于Hsp70、cyclin E和p27的失调，而Hsp70的敲低显著抑制病毒复制。细胞周期在G1期停滞有利于CVB3感染，因为在G1期同步的细胞中病毒复制显著增加。综上所述，本研究表明CVB3的VP1通过上调Hsp70诱导细胞周期阻滞在G1期。我们的研究结果表明，CVB的衣壳蛋白VP1能够在病毒感染期间操纵细胞活动。
Manipulating cell cycle is one of the common strategies used by viruses to generate favorable cellular environment to facilitate viral replication. Coxsackievirus B (CVB) is one of the major viral pathogens of human myocarditis and cardiomyopathy. Because of its small genome, CVB depends on cellular machineries for productive replication. However, how the structural and non-structural components of CVB would manipulate cell cycle is not clearly understood. In this study, we demonstrated that the capsid protein VP1 of CVB type 3 (CVB3) induced cell cycle arrest at G1 phase. G1 arrest was the result of the decrease level of cyclin E and the accumulation of p27Kip1. Study on the gene expression profile of the cells expressing VP1 showed that the expression of both heat shock protein 70-1 (Hsp70-1) and Hsp70-2 was significantly up-regulated. Knockdown of Hsp70 resulted in the increased level of cyclin E and the reduction of p27Kip1. We further demonstrated that the phosphorylation of the heat shock factor 1, which directly promotes the expression of Hsp70, was also increased in the cell expressing VP1. Moreover, we show that CVB3 infection also induced G1 arrest, likely due to dysregulating Hsp70, cyclin E, and p27, while knockdown of Hsp70 dramatically inhibited viral replication. Cell cycle arrest at G1 phase facilitated CVB3 infection, since viral replication in the cells synchronized at G1 phase dramatically increased. Taken together, this study demonstrates that the VP1 of CVB3 induces cell cycle arrest at G1 phase through up-regulating Hsp70. Our findings suggest that the capsid protein VP1 of CVB is capable of manipulating cellular activities during viral infection.