The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB through TRAF6 and TAK1

J Biol Chem. 2006 Jan 27;281(4):2162-9. doi: 10.1074/jbc.M505903200. Epub 2005 Nov 8.

Abstract

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for EBV-mediated B cell transformation. LMP1 is capable of activating several intracellular signaling pathways including the NF-kappaB pathway, which contributes to the EBV-mediated cell transformation. Two regions in the cytoplasmic carboxyl tail of LMP1, namely C-terminal activating regions 1 and 2 (CTAR1 and CTAR2), are responsible for NF-kappaB activation, with CTAR2 being the main NF-kappaB activator. Although the CTAR1-mediated NF-kappaB activation was previously shown to be TRAF3-dependent, we showed here that the CTAR2-mediated NF-kappaB activation is mainly TRAF6-dependent but TRAF2/5-independent. In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappaB pathways, the CTAR2-mediated NF-kappaB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement. Furthermore, we showed that TAK1 is required for NF-kappaB activation by LMP1. Thus, LMP1 utilizes two distinct pathways to activate NF-kappaB: a major one through CTAR2/TRAF6/TAK1/IKKbeta (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKKalpha (noncanonical pathway).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • B-Lymphocytes / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic
  • Genes, Reporter
  • Humans
  • I-kappa B Kinase / metabolism
  • Interleukin-1 Receptor-Associated Kinases
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Luciferases / metabolism
  • MAP Kinase Kinase Kinases / metabolism*
  • Myeloid Differentiation Factor 88
  • NF-kappa B / metabolism*
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Transcriptional Activation
  • Transfection
  • Viral Matrix Proteins / chemistry*
  • Viral Matrix Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • Viral Matrix Proteins
  • Luciferases
  • IRAK1 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7