Document Type
Article
Publication Date
3-1-2017
Identifier
PMCID: PMC5354443 DOI: 10.1371/journal.ppat.1006266
Abstract
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.
Journal Title
PLoS Pathog
Volume
13
Issue
3
First Page
1006266
Last Page
1006266
MeSH Keywords
Ataxia Telangiectasia Mutated Proteins; Blotting, Western; CDC2 Protein Kinase; Cell Line; Cyclin-Dependent Kinases; Erythroid Precursor Cells; Flow Cytometry; G2 Phase Cell Cycle Checkpoints; Humans; Immunoprecipitation; Oligonucleotide Array Sequence Analysis; Parvoviridae Infections; Parvovirus B19, Human; Signal Transduction; Viral Nonstructural Proteins; cdc25 Phosphatases
Recommended Citation
Xu P, Zhou Z, Xiong M, et al. Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway. PLoS Pathog. 2017;13(3):e1006266. Published 2017 Mar 6. doi:10.1371/journal.ppat.1006266
Comments
Grant support
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher's Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006266