Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6

Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15595-600. doi: 10.1073/pnas.2136756100. Epub 2003 Dec 12.


Epstein-Barr virus latent membrane protein 1 (LMP1) activation of NF-kappaB is critical for Epstein-Barr virus-infected B lymphocyte survival. LMP1 activates the IkappaB kinase complex and NF-kappaB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKalpha, IKKbeta, IKKgamma, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-kappaB activation. LMP1-induced RelA nuclear translocation was similar in IKKalpha knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKbeta KO MEFs. NF-kappaB-dependent promoter responses were also substantially deficient in IKKbeta KO MEFs but were hyperactive in IKKalpha KO MEFs. More surprisingly, NF-kappaB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKgamma KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-kappaB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKalpha in IKKbeta regulation, identify an unusual IKKbeta-dependent and IKKgamma-independent NF-kappaB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-kappaB activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • B-Lymphocytes / physiology*
  • B-Lymphocytes / virology
  • Cell Line
  • Cell Nucleus / metabolism
  • Genes, Reporter
  • Herpesvirus 4, Human / physiology
  • Humans
  • Interleukin-1 Receptor-Associated Kinases
  • Luciferases / genetics
  • NF-kappa B / metabolism*
  • Protein Kinases / metabolism*
  • Protein Transport
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Transfection
  • Viral Matrix Proteins / metabolism*


  • EBV-associated membrane antigen, Epstein-Barr virus
  • NF-kappa B
  • Proteins
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 6
  • Viral Matrix Proteins
  • Luciferases
  • Protein Kinases
  • IRAK1 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases