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

AUTOR(ES)

Yasui, Teruhito

FONTE

National Academy of Sciences

RESUMO

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-κB activation. LMP1TM1-2 enabled ≈40% of wild-type LMP1 cytoplasmic domain-mediated NF-κB 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 FWLY38–41 to be critical for LMP1TM1-2 intermolecular association with LMP1TM3-6. Further, in contrast to wild-type LMP1, LMP1 with FWLY38–41 mutated to AALA38–41 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-κB, 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 FWLY38–41 was essential for LMP1-mediated signal transduction, and LMP1 activation of NF-κB is essential for proliferating B lymphocyte survival, inhibition of LMP1FWLY41-mediated LMP1/LMP1 intermolecular interactions is an attractive therapeutic target.

Documentos Relacionados

• Herpes Simplex Virus Tegument Protein VP22 Contains Overlapping Domains for Cytoplasmic Localization, Microtubule Interaction, and Chromatin Binding
• Molecular Dissection of a Yeast Septin: Distinct Domains Are Required for Septin Interaction, Localization, and Function
• Transformation by the oncogenic latent membrane protein correlates with its rapid turnover, membrane localization, and cytoskeletal association.
• Transmembrane Domains 1 and 2 of the Latent Membrane Protein 1 of Epstein-Barr Virus Contain a Lipid Raft Targeting Signal and Play a Critical Role in Cytostasis
• Sorting of yeast alpha 1,3 mannosyltransferase is mediated by a lumenal domain interaction, and a transmembrane domain signal that can confer clathrin-dependent Golgi localization to a secreted protein.