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

Peng, Xiaojue; Zhou, Zhe; Xiong, Min; Zou, Wei; Deng, Xuefeng; Ganaie, Safder S.; Kleiboeker, Steve; Peng, Jianxin; Liu, Kaiyu; Wang, Shengqi; Ye, Shui Qing; Qiu, Jianming

doi:10.1371/journal.ppat.1006266

Cited by 48 publications

(62 citation statements)

References 76 publications

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“…A UT7/Epo-S1 cell line expressing B19V NS1 protein (NS1-S1) was cultured under the same conditions, except that 5 μg/ml doxycycline was used to induce NS1 expression when needed [29]. …”

Section: Methodsmentioning

confidence: 99%

Phosphorylated STAT5 directly facilitates parvovirus B19 DNA replication in human erythroid progenitors through interaction with the MCM complex

et al. 2017

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Productive infection of human parvovirus B19 (B19V) exhibits high tropism for burst forming unit erythroid (BFU-E) and colony forming unit erythroid (CFU-E) progenitor cells in human bone marrow and fetal liver. This exclusive restriction of the virus replication to human erythroid progenitor cells is partly due to the intracellular factors that are essential for viral DNA replication, including erythropoietin signaling. Efficient B19V replication also requires hypoxic conditions, which upregulate the signal transducer and activator of transcription 5 (STAT5) pathway, and phosphorylated STAT5 is essential for virus replication. In this study, our results revealed direct involvement of STAT5 in B19V DNA replication. Consensus STAT5-binding elements were identified adjacent to the NS1-binding element within the minimal origins of viral DNA replication in the B19V genome. Phosphorylated STAT5 specifically interacted with viral DNA replication origins both in vivo and in vitro, and was actively recruited within the viral DNA replication centers. Notably, STAT5 interacted with minichromosome maintenance (MCM) complex, suggesting that STAT5 directly facilitates viral DNA replication by recruiting the helicase complex of the cellular DNA replication machinery to viral DNA replication centers. The FDA-approved drug pimozide dephosphorylates STAT5, and it inhibited B19V replication in ex vivo expanded human erythroid progenitors. Our results demonstrated that pimozide could be a promising antiviral drug for treatment of B19V-related diseases.

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“…A UT7/Epo-S1 cell line expressing B19V NS1 protein (NS1-S1) was cultured under the same conditions, except that 5 μg/ml doxycycline was used to induce NS1 expression when needed [29]. …”

Section: Methodsmentioning

confidence: 99%

Phosphorylated STAT5 directly facilitates parvovirus B19 DNA replication in human erythroid progenitors through interaction with the MCM complex

et al. 2017

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“…In addition, SCH is closely associated with disturbances in lipid metabolism [22, 23], and dyslipidemia is a risk factor of NAFLD [24–26]. We further conducted subgroup analysis to assess the effect of LT 4 supplementation on NAFLD in mild SCH patients with dyslipidemia.…”

Section: Introductionmentioning

confidence: 99%

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients

Liu

Zhao

et al. 2017

International Journal of Endocrinology

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Objectives. To evaluate the effect of levothyroxine (LT4) replacement therapy on nonalcoholic fatty liver disease (NAFLD) in subclinical hypothyroidism (SCH) patients. Methods. This study was a post hoc analysis of a randomized controlled trial and involved 33 significant and 330 mild SCH patients. All of the significant SCH patients received LT4 supplement. The mild SCH patients were grouped as LT4 treated or not. After 15 months of follow-up, prevalence of NAFLD in each group was reevaluated. Subgroup analysis was conducted in mild SCH patients with dyslipidemia. Results. After treatment with LT4, the prevalence of NAFLD in significant SCH patients reduced from 48.5% to 24.2% (p = 0.041). In mild SCH patients, prevalence of NAFLD and serum alanine aminotransferase (ALT) was not significantly affected by LT4 supplementation. Nonetheless, mild SCH patients with dyslipidemia who received LT4 treatment experienced decreases in the prevalence of NAFLD and serum ALT levels (p < 0.05 for both). In contrast, these parameters remained comparably stable in patients who were not treated. Conclusion. LT4 supplementation has benefits on NAFLD in significant SCH patients or mild SCH patients with dyslipidemia. For NAFLD patients with SCH, appropriate supplementation of LT4 may be an effective means of controlling NAFLD. The original trial was registered with ClinicalTrials.gov (NCT01848171).

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“…Electroporation. Two million UT7/Epo-S1 cells were electroporated with 3 g of SalI-linearized B19V infectious clone pM20 (48) in solution V using the Amaxa Nucleofector technology (Lonza, Basel, Switzerland), as described previously (29). After electroporation, the cells were cultured under hypoxic conditions (1% O 2 and 5% CO 2 ) for 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometry. To detect B19V capsid-expressing cells, infected or transfected cells were collected, fixed, and permeabilized as described previously (29). A mouse anti-B19V capsid monoclonal antibody (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development

Peng

Ganaie

Wang

et al. 2019

Antimicrob Agents Chemother

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Human parvovirus B19 (B19V), a member of the genus Erythroparvovirus of the family Parvoviridae, is a small nonenveloped virus that has a single-stranded DNA (ssDNA) genome of 5.6 kb with two inverted terminal repeats (ITRs). B19V infection often results in severe hematological disorders and fetal death in humans. B19V replication follows a model of rolling hairpin-dependent DNA replication, in which the large nonstructural protein NS1 introduces a site-specific single-strand nick in the viral DNA replication origins, which locate at the ITRs. NS1 executes endonuclease activity through the N-terminal origin-binding domain. Nicking of the viral replication origin is a pivotal step in rolling hairpin-dependent viral DNA replication. Here, we developed a fluorophore-based in vitro nicking assay of the replication origin using the origin-binding domain of NS1 and compared it with the radioactive in vitro nicking assay. We used both assays to screen a set of small-molecule compounds (n ϭ 96) that have potential antinuclease activity. We found that the fluorophore-based in vitro nicking assay demonstrates sensitivity and specificity values as high as those of the radioactive assay. Among the 96 compounds, we identified 8 which have an inhibition of Ͼ80% at 10 M in both the fluorophore-based and radioactive in vitro nicking assays. We further tested 3 compounds that have a flavonoid-like structure and an in vitro 50% inhibitory concentration that fell in the range of 1 to 3 M. Importantly, they also exhibited inhibition of B19V DNA replication in UT7/Epo-S1 cells and ex vivo-expanded human erythroid progenitor cells.

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

Cited by 48 publications

References 76 publications

Phosphorylated STAT5 directly facilitates parvovirus B19 DNA replication in human erythroid progenitors through interaction with the MCM complex

Phosphorylated STAT5 directly facilitates parvovirus B19 DNA replication in human erythroid progenitors through interaction with the MCM complex

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients

Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development

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