Hepatitis C virus-mediated Aurora B kinase inhibition modulates inflammatory pathway and viral infectivity.
OBJECTIVE
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.
Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria "La Paz", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain.
Antonio
A
Madejón
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain.
Julie
J
Sheldon
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Irene
I
Francisco-Recuero
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain.
Celia
C
Perales
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Mariela
M
Domínguez-Beato
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Marina
M
Lasa
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Isabel
I
Sánchez-Perez
Oncology Surgery, Cell Therapy and Transplant Organs, Institute of Biomedicine of Seville (IBiS)-Virgen del Rocio Universitary Hospital (CSIC), University of Seville, Seville, Spain.
Jordi
J
Muntané
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain.
Esteban
E
Domingo
Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria "La Paz", Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Salud Carlos III, Madrid, Spain.
Javier
J
García-Samaniego
Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Electronic address: asanchez@iib.uam.es.
Aurora
A
Sánchez-Pacheco
D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001706:Biopsy; D015153:Blotting, Western; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D012367:RNA, Viral / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D012367:RNA, Viral; D064107:Aurora Kinase B
COX-2; Hepatitis C; Histone modifications; Inflammation; NF-κB