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Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication
- Source :
- Hepatology, Hepatology, Wiley-Blackwell, 2017, ⟨10.1002/hep.29236⟩
- Publication Year :
- 2016
-
Abstract
- Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for chronic hepatitis B and HCC are suboptimal. Herein, we identified cellular serine/threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of primary human hepatocytes (PHHs) and differentiated HepaRG cells in conjunction with pharmacologic PLK1 inhibitors, small interfering RNA (siRNA)-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA ). In addition, a humanized liver Fah-/- /Rag2-/- /Il2rg-/- (FRG) mouse model was used to determine the antiviral effect of PLK1 inhibitor BI-2536 on HBV infection in vivo. Finally, in vitro PLK1 kinase assays and site-directed mutagenesis were employed to demonstrate that HBV core protein (HBc) is a PLK1 substrate. We demonstrated that HBV infection activated cellular PLK1 in PHHs and differentiated HepaRG cells. PLK1 inhibition by BI-2536 or siRNA-mediated knockdown suppressed HBV DNA biosynthesis, whereas overexpression of PLK1CA increased it, suggesting that the PLK1 effects on viral biosynthesis are specific and that PLK1 is a proviral cellular factor. Significantly, BI-2536 administration to HBV-infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as an antiviral target in vivo. The proviral action of PLK1 is associated with the biogenesis of the nucleocapsid, as BI-2536 leads to its decreased intracellular formation/accumulation. In this respect, our studies identified HBc as a PLK1 substrate in vitro, and mapped PLK1 phosphorylation sites on this protein. Conclusion PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and antitumoral strategies against HBV infection and HBV-mediated carcinogenesis. (Hepatology 2017;66:1750-1765).
- Subjects :
- 0301 basic medicine
Risk
Small interfering RNA
Hepatitis B virus
Carcinogenesis
Cells
Primary Cell Culture
Drug Evaluation, Preclinical
[SDV.CAN]Life Sciences [q-bio]/Cancer
Cell Cycle Proteins
Biology
Protein Serine-Threonine Kinases
medicine.disease_cause
Virus Replication
Hepatitis B virus PRE beta
Virus
Hepatitis
03 medical and health sciences
Mice
In vivo
Proto-Oncogene Proteins
medicine
Animals
Humans
Amino Acid Sequence
Phosphorylation
Host factor
Hepatology
Kinase
Pteridines
Viral Core Proteins
Carcinoma
virus diseases
Dna
Hepatitis B
Virology
digestive system diseases
3. Good health
Enzyme Activation
030104 developmental biology
Viral replication
Liver
Mutagenesis
Host-Pathogen Interactions
Hepatocytes
France
biosynthesis
Infection
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 66
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Hepatology (Baltimore, Md.)
- Accession number :
- edsair.doi.dedup.....96729e496aa1fa64f514f6b6dfa6a025