The noncanonical NF-κB pathway

Immunol Rev. 2012 Mar;246(1):125-40. doi: 10.1111/j.1600-065X.2011.01088.x.


The noncanonical nuclear factor-κB (NF-κB) signaling pathway mediates activation of the p52/RelB NF-κB complex and, thereby, regulates specific immunological processes. This NF-κB pathway relies on the inducible processing of NF-κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF-κB pathway. A central signaling component of the noncanonical NF-κB pathway is NF-κB-inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF-κB kinase α), to induce phosphorylation-dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor-associated factor-3 (TRAF3)-dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF-κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF-κB pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Humans
  • NF-kappa B / metabolism*
  • NF-kappa B p52 Subunit / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction*


  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase