title: HBV secretion is regulated through the activation of endocytic and autophagic compartments mediated by Rab7 stimulation.
abstract: The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characterized by the formation of numerous tubules that are dependent upon the increase in Rab7 activity observed in the HBV-expressing HepG2.2.15 cells compared to HepG2 cells. Interestingly, transfection-based expression of the five individual viral proteins indicated that the precore protein, which is a precursor of HBeAg, was largely responsible for the increased Rab7 activity. Finally, small interfering RNA (siRNA)-mediated depletion of Rab7 significantly increased the secretion of virions, suggesting that reduced delivery of the virus to the lysosome facilitates viral secretion. These findings provide novel evidence indicating that HBV can regulate its own secretion through an activation of the endo-lysosomal and autophagic pathway mediated by Rab7 activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Krueger
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ninomiya
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA mcniven.mark@mayo.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
mesh_terms: D000956:Antigens, Viral / Q000378:metabolism; D001343:Autophagy; D002451:Cell Compartmentation; D004705:Endocytosis; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000473:pathology / Q000821:virology; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008561:Membrane Fusion; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000956:Antigens, Viral; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020691:rab GTP-Binding Proteins
keywords: Autophagosome; HBV; MVB; Rab7; Tubule