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

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 Liu^1,2,3, Qingqing Li¹, Xiaoxin Li^1,4, Zhenzhen Qiu^1,5, Andrew Li⁶, Wenhan Liang¹, Huangyao Chen¹, Xiangsheng Cai^1,7, Xinglu Chen^1,7, Xinyue Duan¹, Jingjing Li¹, Wangsheng Wu^1,8, Mingyu Xu¹, Yingying Mao¹, Huiying Chen¹, Jinlong Li¹, Weiwang Gu^2,9,10,11✉, Hongwei Li^1✉

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.

✉ Corresponding authors: Weiwang Gu, MS, Institute of Comparative Medicine and Center of Laboratory Animals, Southern Medical University, 1023 South Shatai Road, Guangzhou, Guangdong 510515, China. Phone: 86-20-61648043; Fax: 86-20-61648043; E-mail: guww100com; Hongwei Li, Ph.D., School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 South Shatai Road, Guangzhou, Guangdong 510515, China. Phone: 86-20-61648555; Fax: 86-20-61648555; E-mail: lihwedu.cn More

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 p21^Cip1/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

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