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Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation.

Publication ,  Journal Article
Luftig, M; Yasui, T; Soni, V; Kang, M-S; Jacobson, N; Cahir-McFarland, E; Seed, B; Kieff, E
Published in: Proc Natl Acad Sci U S A
January 6, 2004

Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced NF-kappaB activation is important for infected cell survival. LMP1 activates NF-kappaB, in part, by engaging tumor necrosis factor (TNF) receptor-associated factors (TRAFs), which also mediate NF-kappaB activation from LTbetaR and CD40. LTbetaR and CD40 activation of p100/NF-kappaB2 is now known to be NIK/IKKalpha-dependent and IKKbeta/IKKgamma independent. In the experiments described here, we found that EBV LMP1 induced p100/NF-kappaB2 processing in human lymphoblasts and HEK293 cells. LMP1-induced p100 processing was NIK/IKKalpha dependent and IKKbeta/IKKgamma independent. Furthermore, the LMP1 TRAF-binding site was required for p100 processing and p52 nuclear localization, whereas the LMP1 death domain-binding site was not. Moreover, the LMP1 TRAF-binding site preferentially caused RelB nuclear accumulation. In murine embryo fibroblasts (MEFs), IKKbeta was essential for LMP1 up-regulation of macrophage inflammatory protein (MIP)-2, TNFalpha, I-TAC, ELC, MIG, and CXCR4 RNAs. Interestingly, in IKKalpha knockout MEFs, LMP1 hyperinduced MIP-2, TNFalpha, and I-TAC expression, consistent with a role for IKKalpha in down-modulating canonical IKKbeta activation or its effects. In contrast, LMP1 failed to up-regulate CXCR4 and MIG RNA in IKKalpha knockout MEFs, indicating a dependence on noncanonical IKKalpha activation. Furthermore, LMP1 up-regulation of MIP-2 RNA in MEFs was both IKKbeta- and IKKgamma-dependent, whereas LMP1 upregulation of MIG and I-TAC RNA was fully IKKgamma independent. Thus, LMP1 induces typical canonical IKKbeta/IKKgamma-dependent, atypical canonical IKKbeta-dependent/IKKgamma-independent, and noncanonical NIK/IKKalpha-dependent NF-kappaB activations; NIK/IKKalpha-dependent NF-kappaB activation is principally mediated by the LMP1 TRAF-binding site.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

January 6, 2004

Volume

101

Issue

1

Start / End Page

141 / 146

Location

United States

Related Subject Headings

  • Viral Matrix Proteins
  • TNF Receptor-Associated Factor 1
  • RNA
  • Proteins
  • Protein Serine-Threonine Kinases
  • Protein Processing, Post-Translational
  • NF-kappaB-Inducing Kinase
  • NF-kappa B
  • Models, Biological
  • Mice
 

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Luftig, M., Yasui, T., Soni, V., Kang, M.-S., Jacobson, N., Cahir-McFarland, E., … Kieff, E. (2004). Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. Proc Natl Acad Sci U S A, 101(1), 141–146. https://doi.org/10.1073/pnas.2237183100
Luftig, Micah, Teruhito Yasui, Vishal Soni, Myung-Soo Kang, Nils Jacobson, Ellen Cahir-McFarland, Brian Seed, and Elliott Kieff. “Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation.Proc Natl Acad Sci U S A 101, no. 1 (January 6, 2004): 141–46. https://doi.org/10.1073/pnas.2237183100.
Luftig M, Yasui T, Soni V, Kang M-S, Jacobson N, Cahir-McFarland E, et al. Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):141–6.
Luftig, Micah, et al. “Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation.Proc Natl Acad Sci U S A, vol. 101, no. 1, Jan. 2004, pp. 141–46. Pubmed, doi:10.1073/pnas.2237183100.
Luftig M, Yasui T, Soni V, Kang M-S, Jacobson N, Cahir-McFarland E, Seed B, Kieff E. Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):141–146.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

January 6, 2004

Volume

101

Issue

1

Start / End Page

141 / 146

Location

United States

Related Subject Headings

  • Viral Matrix Proteins
  • TNF Receptor-Associated Factor 1
  • RNA
  • Proteins
  • Protein Serine-Threonine Kinases
  • Protein Processing, Post-Translational
  • NF-kappaB-Inducing Kinase
  • NF-kappa B
  • Models, Biological
  • Mice