Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein.
Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28gamma (11S regulator gamma) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28gamma with other Flavivirus core proteins was detected. Deletion of the PA28gamma-binding region from the HCV core protein or knockout of the PA28gamma gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28gamma enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28gamma-dependent pathway through which HCV pathogenesis may be exerted.
Moriishi
Kohji
K
Research Center for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka 565-0871, Japan.
Okabayashi
Tamaki
T
Nakai
Kousuke
K
Moriya
Kyoji
K
Koike
Kazuhiko
K
Murata
Shigeo
S
Chiba
Tomoki
T
Tanaka
Keiji
K
Suzuki
Ryosuke
R
Suzuki
Tetsuro
T
Miyamura
Tatsuo
T
Matsuura
Yoshiharu
Y
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001324:Autoantigens; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D015723:Gene Library; D016174:Hepacivirus / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D014758:Viral Core Proteins / Q000737:chemistry / Q000378:metabolism*
D001324:Autoantigens; C099558:Ki antigen; D009687:Nuclear Proteins; D014758:Viral Core Proteins; D046988:Proteasome Endopeptidase Complex