title: LMP1 transmembrane domain 1 and 2 (TM1-2) FWLY mediates intermolecular interactions with TM3-6 to activate NF-kappaB.
abstract: The Epstein-Barr virus oncoprotein LMP1 has six transmembrane domains (TMs) that enable intermolecular aggregation and constitutive signaling through two C-terminal cytosolic domains. Expression of both TMs 1 and 2 without the C terminus (TM1-2DeltaC) and TMs 3 to 6 fused to the C terminus (TM3-6) results in partial association, which is substantially decreased by TM1 F38WLY41 mutation to A38ALA41. We now investigate whether TM1-2DeltaC can functionally interact with TM3-6. TM1-2DeltaC induced TM3-6 to mediate NF-kappaB activation at 59% of LMP1 levels, and the effect was dependent on TM1-2 F38WLY41. TM1-2DeltaC even induced TM3-4 C terminus-mediated NF-kappaB activation to 44% of LMP1 levels. Surprisingly, this effect was TM1 F38WLY41 independent, indicative of a role for TMs 5 and 6 in TM1 F38WLY41 effects. TM3 W98 was also important for TM1-2DeltaC induction of TM3-6-mediated NF-kappaB activation, for association, and for TM1 F38WLY41 dependence on C-terminal NF-kappaB activation. These data support models in which the TM1 F38WLY41 effects are at least partially dependent on TM3 W98 and a residue(s) in TMs 5 and 6.
authors.affiliation: Channing Laboratory and Infectious Disease Division, Brigham and Women's Hospital, Boston, MA 02130, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Soni
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Ellen
authors.initials: E
authors.lastname: Cahir-McFarland
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins