Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase

Immunity. 2004 Oct;21(4):477-89. doi: 10.1016/j.immuni.2004.08.009.


The NF-kappaB-inducing kinase (NIK) induces proteolytic processing of NF-kappaB2/p100 and, hence, the generation of NF-kappaB dimers such as p52:RelB but was suggested not to signal for the processing of IkappaB. Here, we show that although the induction of IkappaB degradation in lymphocytes by TNF is independent of NIK, its induction by CD70, CD40 ligand, and BLyS/BAFF, which all also induce NF-kappaB2/p100 processing, does depend on NIK function. Both CD70 and TNF induce recruitment of the IKK kinase complex to their receptors. In the case of CD70, but not TNF, this process is associated with NIK recruitment and is followed by prolonged receptor association of just IKK1 and NIK. Recruitment of the IKK complex to CD27, but not that of NIK, depends on NIK kinase function. Our findings indicate that NIK participates in a unique set of proximal signaling events initiated by specific inducers, which activate both canonical and noncanonical NF-kappaB dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • B-Cell Activating Factor
  • CD27 Ligand
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Cell Line, Tumor
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / immunology
  • I-kappa B Proteins / metabolism
  • Immunoblotting
  • Immunoprecipitation
  • Lymphocyte Activation / immunology*
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Models, Immunological
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / immunology*
  • Transfection
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antigens, CD
  • B-Cell Activating Factor
  • CD27 Ligand
  • CD70 protein, human
  • I-kappa B Proteins
  • Membrane Proteins
  • NF-kappa B
  • TNFSF13B protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • NF-kappa B kinase