title: Human herpesvirus 6 glycoprotein complex formation is required for folding and trafficking of the gH/gL/gQ1/gQ2 complex and its cellular receptor binding.
abstract: Human herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. A glycoprotein (g) complex that is unique to HHV-6, gH/gL/gQ1/gQ2, is a viral ligand for its cellular receptor, human CD46. However, whether complex formation or one component of the complex is required for CD46 binding and how the complex is transported in cells are open questions. Furthermore, in HHV-6-infected cells the gQ1 protein modified with N-linked glycans is expressed in two forms with different molecular masses: an 80-kDa form (gQ1-80K) and a 74-kDa form (gQ1-74K). Only gQ1-80K, but not gQ1-74K, forms the complex with gQ2, gH, and gL, and this four-component complex is incorporated into mature virions. Here, we characterized the molecular context leading to the maturation of gQ1 by expressing combinations of the individual gH/gL/gQ1/gQ2 components in 293T cells. Surprisingly, only when all four molecules were expressed was a substantial amount of gQ1-80K detected, indicating that all three of the other molecules (gQ2, gH, and gL) were necessary and sufficient for gQ1 maturation. We also found that only the tetrameric complex, and not its subsets, binds to CD46. Finally, a gQ2-null virus constructed in the BAC (bacterial artificial chromosome) system could not be reconstituted, indicating that gQ2 is essential for virus growth. These results show that gH, gL, gQ1, and gQ2 are all essential for the trafficking and proper folding of the gH/gL/gQ1/gQ2 complex and, thus, for HHV-6 infection.
authors.affiliation: Division of Clinical Virology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Huamin
authors.initials: H
authors.lastname: Tang
authors.forename: Mayuko
authors.initials: M
authors.lastname: Hayashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeki
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamanishi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mori
mesh_terms: D002460:Cell Line; D020043:Genes, Essential; D005814:Genes, Viral; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D021381:Protein Transport; D011991:Receptors, Virus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C497857:CD46 protein, human; D006023:Glycoproteins; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus; D014764:Viral Proteins