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Int J Biol Sci 2018; 14(9):1099-1108. doi:10.7150/ijbs.26400

Research Paper

Zika Virus Envelope Protein induces G2/M Cell Cycle Arrest and Apoptosis via an Intrinsic Cell Death Signaling Pathway in Neuroendocrine PC12 Cells

Jun Liu1,2,3, Qingqing Li1, Xiaoxin Li1,4, Zhenzhen Qiu1,5, Andrew Li6, Wenhan Liang1, Huangyao Chen1, Xiangsheng Cai1,7, Xinglu Chen1,7, Xinyue Duan1, Jingjing Li1, Wangsheng Wu1,8, Mingyu Xu1, Yingying Mao1, Huiying Chen1, Jinlong Li1, Weiwang Gu2,9,10,11✉, Hongwei Li1✉

1. School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
2. Institute of Comparative Medicine and Center of Laboratory Animals, Southern Medical University, Guangzhou, China.
3. Dermatology Hospital of Southern Medical University, Guangzhou, China.
4. Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
5. Guangzhou Bioneeds Biotechnology Co., Ltd, Guangzhou, China.
6. Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, USA.
7. Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
8. Animal Science and Technology College, Jilin Agricultural University, Changchun, China.
9. Pearl Lab Animal Science and Technology Co. Ltd, Dongguang, China.
10. School of Chemical and Environmental Engineering, Wuyi University, Jiangmen, China.
11. International Healthcare Innovation Institute, Jiangmen, China.

Abstract

Clinical evidence suggests that there exists a strong correlation between Zika virus (ZIKV) infection and abnormal development of the nervous system. However, the underlying mechanisms remain to be elusive. In this study, recombinant lentiviral vectors coding for ZIKV structural proteins and truncations (prM-Env, M-Env and Env) were transduced into PC12 cells. Envelope (Env) overexpression induced significant inhibition of proliferation and triggered G2/M cell cycle arrest and apoptosis in PC12 cells. Flow cytometry and western blot analysis showed that the apoptosis was associated with up-regulation of both p53 and p21Cip1/Waf1 and down-regulation of cyclin B1. Presence of aberrant nuclei clusters were confirmed by immunofluorescence staining analysis. The data indicate that overexpression of prM-Env, M-Env or Env led to apoptosis via an intrinsic cell death signaling pathway that is dependent on the activation of caspase-9 and caspase-3 and accompanied by an increased ratio of Bax to Bcl-2 in transduced PC12 cells. In summary, our results suggest that ZIKV Env protein causes apoptosis in PC12 cells via an intrinsic cell death signaling pathway, which may contribute to ZIKV-induced abnormal development of the nervous system.

Keywords: ZIKV, envelope protein, G2/M arrest, mitotic catastrophe, apoptosis

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Liu J, Li Q, Li X, Qiu Z, Li A, Liang W, Chen H, Cai X, Chen X, Duan X, Li J, Wu W, Xu M, Mao Y, Chen H, Li J, Gu W, Li H. Zika Virus Envelope Protein induces G2/M Cell Cycle Arrest and Apoptosis via an Intrinsic Cell Death Signaling Pathway in Neuroendocrine PC12 Cells. Int J Biol Sci 2018; 14(9):1099-1108. doi:10.7150/ijbs.26400. Available from http://www.ijbs.com/v14p1099.htm