Nonstructural 3/4A protease of hepatitis C virus activates epithelial growth factor-induced signal transduction by cleavage of the T-cell protein tyrosine phosphatase.
The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A.


CONCLUSIONS
This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication.
Brenndörfer
Erwin Daniel
ED
Department of Gastroenterology, Hepatology and Infectiology, University Hospital, Heinrich-Heine-University of Düsseldorf, Germany.
Karthe
Juliane
J
Frelin
Lars
L
Cebula
Patricia
P
Erhardt
Andreas
A
Schulte am Esch
Jan
J
Hengel
Hartmut
H
Bartenschlager
Ralf
R
Sällberg
Matti
M
Häussinger
Dieter
D
Bode
Johannes Georg
JG
D000328:Adult; D000368:Aged; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000502:physiology*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology*
D017361:Viral Nonstructural Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D010447:Peptide Hydrolases