title: Characterization of α-taxilin as a novel factor controlling the release of hepatitis C virus.
abstract: 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.
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Elgner
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Donnerhak
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Huimei
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Medvedev
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Weber
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilmann
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ploen
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Himmelsbach
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Malin
authors.initials: M
authors.lastname: Finkernagel
authors.affiliation: Department of Molecular Pathology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany Deutsches Zentrum für Infektionsforschung (DZIF), Inhoffenstraße 7, 38124 Braunschweig, Germany eberhard.hildt@pei.de.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Hildt
mesh_terms: D056945:Hep G2 Cells; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D013572:Synaptic Vesicles / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000096:biosynthesis*
chemical_list: C488100:TXLNA protein, human; D033921:Vesicular Transport Proteins
keywords: HCV; SNARE; morphogenesis; signal transduction; α-taxilin