Background & Aims
Chronic hepatitis C is a leading cause of chronic liver disease, cirrhosis and hepatocellular
carcinoma. DNA methylation and histone covalent modifications constitute crucial mechanisms
of genomic instability in human disease, including liver fibrosis and hepatocellular
carcinoma. The present work studies the consequences of HCV-induced histone modifications
in early stages of infection.
Methods
Human primary hepatocytes and HuH7.5 cells were transiently transfected with the core
protein of hepatitis C virus (HCV) genotypes 1a, 1b, and 2a. Infectious genotype 2a
HCV in culture was also used.
Results
We show that HCV and core protein inhibit the phosphorylation of Serine 10 in histone
3. The inhibition is due to the direct interaction between HCV core and Aurora B kinase
(AURKB) that results in a decrease of AURKB activity. HCV and core significantly downregulate
NF-κB and COX-2 transcription, two proteins with anti-apoptotic and proliferative
effects implicated in the control of the inflammatory response. AURKB depletion reduced
HCV and core repression of NF-κB and COX-2 gene transcription and AURKB overexpression
reversed the viral effect. AURKB abrogation increased HCV specific infectivity which
was decreased when AURKB was overexpressed.
Conclusions
The core-mediated decrease of AURKB activity may play a role in the inflammatory pathway
during the initial steps of viral infection, while ensuring HCV infectivity.
Abbreviations:
HCV (hepatitis C virus), HCC (hepatocellular carcinoma), AURKB (Aurora B kinase), PP2 (protein phosphatase 2), Chk1 (checkpoint kinase 1), NF-κB (nuclear factor-κB), COX-2 (cyclooxygenase-2)Keywords
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Article info
Publication history
Published online: February 28, 2015
Accepted:
February 23,
2015
Received in revised form:
February 16,
2015
Received:
July 31,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
