title: Molecular determinants for subcellular localization of hepatitis C virus core protein.
abstract: Hepatitis C virus (HCV) core protein is a putative nucleocapsid protein with a number of regulatory functions. In tissue culture cells, HCV core protein is mainly located at the endoplasmic reticulum as well as mitochondria and lipid droplets within the cytoplasm. However, it is also detected in the nucleus in some cells. To elucidate the mechanisms by which cellular trafficking of the protein is controlled, we performed subcellular fractionation experiments and used confocal microscopy to examine the distribution of heterologously expressed fusion proteins involving various deletions and point mutations of the HCV core combined with green fluorescent proteins. We demonstrated that a region spanning amino acids 112 to 152 can mediate association of the core protein not only with the ER but also with the mitochondrial outer membrane. This region contains an 18-amino-acid motif which is predicted to form an amphipathic alpha-helix structure. With regard to the nuclear targeting of the core protein, we identified a novel bipartite nuclear localization signal, which requires two out of three basic-residue clusters for efficient nuclear translocation, possibly by occupying binding sites on importin-alpha. Differences in the cellular trafficking of HCV core protein, achieved and maintained by multiple targeting functions as mentioned above, may in part regulate the diverse range of biological roles of the core protein.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, Japan 162-8640.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Suzuki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Takeya
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Akiko
authors.initials: A
authors.lastname: Rikimaru
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimoike
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Miyamura
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000737:chemistry; D016174:Hepacivirus / Q000737:chemistry*; D006801:Humans; D028884:Karyopherins / Q000502:physiology; D008928:Mitochondria / Q000737:chemistry; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D014758:Viral Core Proteins / Q000032:analysis* / Q000737:chemistry
chemical_list: D028884:Karyopherins; D019913:Nuclear Localization Signals; D014758:Viral Core Proteins