Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction, raft localization, and signaling.

Journal Article (Journal Article)

Relatively little is known about the biochemical mechanisms through which the Epstein-Barr virus latent infection integral membrane protein 1 (LMP1) transmembrane domains cause constitutive LMP1 aggregation and continuous cytoplasmic C terminus-mediated signal transduction. We now evaluate the role of the three consecutive LMP1 hydrophobic transmembrane pairs, transmembrane domains (TM)1-2, TM3-4, and TM5-6, in intermolecular aggregation and NF-kappaB activation. LMP1TM1-2 enabled approximately 40% of wild-type LMP1 cytoplasmic domain-mediated NF-kappaB activation, whereas TM3-4 or TM5-6 assayed in parallel had almost no effect independent of LMP1TM1-2. Alanine mutagenesis of conserved residues in LMP1TM1-2 identified FWLY(38-41) to be critical for LMP1TM1-2 intermolecular association with LMP1TM3-6. Further, in contrast to wild-type LMP1, LMP1 with FWLY(38-41) mutated to AALA(38-41) did not (i). significantly partition to lipid Rafts or Barges and effectively intermolecularly associate, (ii). enable cytoplasmic C terminus engagement of tumor necrosis factor receptor-associated factor 3, (iii). activate NF-kappaB, and thereby (iv). induce tumor necrosis factor receptor-associated factor 1 expression. Other LMP1 intermolecular associations were observed that involved LMP1TM1-2/LMP1TM1-2 or LMP1TM3-4/LMP1TM3-6 interactions; these probably also contribute to LMP1 aggregation. Because FWLY(38-41) was essential for LMP1-mediated signal transduction, and LMP1 activation of NF-kappaB is essential for proliferating B lymphocyte survival, inhibition of LMP1FWLY(41)-mediated LMP1/LMP1 intermolecular interactions is an attractive therapeutic target.

Full Text

Duke Authors

Cited Authors

  • Yasui, T; Luftig, M; Soni, V; Kieff, E

Published Date

  • January 6, 2004

Published In

Volume / Issue

  • 101 / 1

Start / End Page

  • 278 - 283

PubMed ID

  • 14695890

Pubmed Central ID

  • PMC314176

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.2237224100


  • eng

Conference Location

  • United States