Although it is well established that the release of HCV (hepatitis C virus) occurs through the secretory pathway, many aspects concerning the control of this process are not yet fully understood. α-Taxilin was identified as a novel binding partner of syntaxin-4 and of other members of the syntaxin family, which are part of SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes and so are involved in intracellular vesicle traffic. Since α-taxilin prevents t-SNARE (target SNARE) formation by binding exclusively to free syntaxin-4, it exerts an inhibitory effect on the vesicular transport. HCV-replicating Huh7.5 cells and HCV-infected primary human hepatocytes and liver samples of patients suffering from chronic HCV contain significantly less α-taxilin compared with the controls. HCV impairs the expression of α-taxilin via NS5A-dependent interruption of the Raf/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] signal transduction cascade. Moreover, the half-life of α-taxilin is significantly reduced in HCV-replicating cells. Whereas modulation of α-taxilin expression does not significantly affect genome replication, the overexpression of α-taxilin prevents the release of HCV. In contrast with this, silencing of α-taxilin expression leads to increased release of infectious viral particles. This is due to the negative effect of α-taxilin on t-SNARE formation that leads to impaired vesicular trafficking. Accordingly, overexpression of the t-SNARE component syntaxin-4 increases release of HCV, whereas silencing leads to an impaired release. These data identify α-taxilin as a novel factor that controls the release of HCV and reveal the mechanism by which HCV controls the activity of α-taxilin.
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Research Article|
January 05 2016
Characterization of α-taxilin as a novel factor controlling the release of hepatitis C virus
Fabian Elgner;
Fabian Elgner
1
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Christian Donnerhak;
Christian Donnerhak
1
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Huimei Ren;
Huimei Ren
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Regina Medvedev;
Regina Medvedev
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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André Schreiber;
André Schreiber
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Lorenz Weber;
Lorenz Weber
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Markus Heilmann;
Markus Heilmann
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Daniela Ploen;
Daniela Ploen
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Kiyoshi Himmelsbach;
Kiyoshi Himmelsbach
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Malin Finkernagel;
Malin Finkernagel
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
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Karin Klingel;
Karin Klingel
†Department of Molecular Pathology, University of Tübingen, 72076 Tübingen, Germany
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Eberhard Hildt
Eberhard Hildt
2
*Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, 63225 Langen, Germany
‡Deutsches Zentrum für Infektionsforschung (DZIF), Inhoffenstraße 7, 38124 Braunschweig, Germany
2To whom correspondence should be addressed (email eberhard.hildt@pei.de).
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Publisher: Portland Press Ltd
Received:
June 23 2015
Revision Received:
October 23 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 Authors; published by Portland Press Limited
2016
Biochem J (2016) 473 (2): 145–155.
Article history
Received:
June 23 2015
Revision Received:
October 23 2015
Accepted:
November 02 2015
Accepted Manuscript online:
November 02 2015
Citation
Fabian Elgner, Christian Donnerhak, Huimei Ren, Regina Medvedev, André Schreiber, Lorenz Weber, Markus Heilmann, Daniela Ploen, Kiyoshi Himmelsbach, Malin Finkernagel, Karin Klingel, Eberhard Hildt; Characterization of α-taxilin as a novel factor controlling the release of hepatitis C virus. Biochem J 15 January 2016; 473 (2): 145–155. doi: https://doi.org/10.1042/BJ20150717
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