Human VAP-C negatively regulates hepatitis C virus propagation.
Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.
Kukihara
Hiroshi
H
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Japan.
Moriishi
Kohji
K
Taguwa
Shuhei
S
Tani
Hideki
H
Abe
Takayuki
T
Mori
Yoshio
Y
Suzuki
Tetsuro
T
Fukuhara
Takasuke
T
Taketomi
Akinobu
A
Maehara
Yoshihiko
Y
Matsuura
Yoshiharu
Y
D002460:Cell Line; D015536:Down-Regulation; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D011485:Protein Binding; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
D033921:Vesicular Transport Proteins; D017361:Viral Nonstructural Proteins; C114051:VAPA protein, human; C496748:VAPB protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase