Abstract
Many viruses disrupt the host cell cycle to facilitate their own growth. We assessed the mechanism and function of enterovirus 71 (EV71), a primary causative agent for recent hand, foot, and mouth disease outbreaks, in manipulating cell cycle progression. Our results suggest that EV71 infection induces S-phase arrest in diverse cell types by preventing the cell cycle transition from the S phase into the G2/M phase. Similar results were observed for an alternate picornavirus, Coxsackievirus A16. Synchronization in S phase, but not G0/G1 phase or G2/M phase, promotes viral replication. Consistent with its ability to arrest cells in S phase, the expression of cyclin A2, CDK 2, cyclin E1, and cyclin B1 was regulated by EV71 through increasing transcription of cyclin E1, promoting proteasome-mediated degradation of cyclin A2 and regulating the phosphorylation of CDK 2. Finally, a non-structural protein of EV71, the RNA-dependent RNA polymerase 3D, was demonstrated to mediate S-phase cell cycle arrest. These findings suggest that EV71 induces S-phase cell cycle arrest in infected cells via non-structural protein 3D, which may provide favorable conditions for virus production.
Disclosure of Potential Conflicts of Interest
There was no conflict of interest for any author.
Acknowledgments
We thank Professors Shih-Yen Lo (Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan) and Jianwei Wang (MOH Key Laboratory of Systems Biology of Pathogens, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China) for providing valuable plasmids and Professor Qi Jin (Institute of Pathogen Biology, Beijing, China) for the gift of CVA16 virus SHZH05.
Funding
This work was mainly supported by funding from National Natural Science Foundation of China (81301416). It was also supported by funding from the Chinese Ministry of Science and Technology (2012CB911100 and 2013ZX10001005), the Jilin Provincial Science and Technology Department (20140204004YY), the State Grade III Laboratory of Traditional Chinese Medicine, Immunology and Molecular Biology Laboratory of Chinese Ministry of Education (IRT1016), The Key Laboratory of Molecular Virology of Jilin Province (20102209), and a grant (2R56AI62644–6) from the NIAID.
Supplemental Material
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