Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway

PLoS Pathogens

Shui Qing Ye¹  Min Xiong¹  Safder S. Ganaie²  Zhe Zhou²  Xuefeng Deng²  Steve Kleiboeker²  Wei Zou³  Jianming Qiu³  Jianxin Peng⁴  Kaiyu Liu⁵  Peng Xu⁵  Shengqi Wang⁵ 

[1] Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China;Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, United States of America;Department of Pediatrics and Department of Biomedical and Health Informatics, The Children’s Mercy Hospital and University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America;Department of Research and Development, Viracor-IBT Laboratories, Lee’s Summit, Missouri, United States of America;School of Life Sciences, Central China Normal University, Wuhan, China

关键词: Cell cycle;    cell division;    Phosphorylation;    Cyclins;    Flow cytometry;    DNA replication;    Gene expression;    Synthesis phase;    Transactivation;   

DOI  :  10.1371/journal.ppat.1006266

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest. The results confirm that the NS1 TAD2 domain plays a pivotal role in NS1-induced G2-phase arrest. Mechanistically, NS1 transactivated cellular gene expression through the TAD2 domain, which was itself responsible for ATR (ataxia-telangiectasia mutated and Rad3-related) activation. Activated ATR phosphorylated CDC25C at serine 216, which in turn inactivated the cyclin B/CDK1 complex without affecting nuclear import of the complex. Importantly, we found that the ATR-CHK1-CDC25C-CDK1 pathway was activated during B19V infection of EPCs, and that ATR activation played an important role in B19V infection-induced G2-phase arrest.

【 授权许可】

CC BY