NF-κB Signaling

Nuclear factor-κB (NF-κB)/Rel proteins include NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, and RelB. These proteins function as dimeric transcription factors that regulate the expression of genes influencing a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis. In the classical (or canonical) pathway, NF-κB/Rel proteins are bound and inhibited by IκB proteins. Proinflammatory cytokines, LPS, growth factors, and antigen receptors activate an IKK complex (IKKβ, IKKα, and NEMO), which phosphorylates IκB proteins. Phosphorylation of IκB leads to its ubiquitination and proteasomal degradation, freeing NF-κB/Rel complexes. Active NF-κB/Rel complexes are further activated by post-translational modifications (phosphorylation, acetylation, glycosylation) and translocate to the nucleus where, either alone or in combination with other transcription factors including AP-1, Ets, and Stat, they induce target gene expression. In the alternative (or noncanonical) NF-κB pathway, NF-κB2 p100/RelB complexes are inactive in the cytoplasm. Signaling through a subset of receptors, including LTβR, CD40, and BR3, activates the kinase NIK, which in turn activates IKKα complexes that phosphorylate C-terminal residues in NF-κB2 p100. Phosphorylation of NF-κB2 p100 leads to its ubiquitination and proteasomal processing to NF-κB2 p52. This creates transcriptionally competent NF-κB p52/RelB complexes that translocate to the nucleus and induce target gene expression. Only a subset of NF-κB agonists and target genes are shown here.

Selected Reviews:

• Gilmore TD (2008) www.nf-kb.org
• Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132(3), 344–62.
• Perkins ND (2006) Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 25(51), 6717–30.
• Sun SC (2012) The noncanonical NF-κB pathway. Immunol. Rev. 246(1), 125–40.
• Chen J, Chen ZJ (2013) Regulation of NF-κB by ubiquitination. Curr. Opin. Immunol. 25(1), 4–12.

We would like to thank Prof. Thomas D. Gilmore, Boston University, Boston, MA, for contributing to this diagram.

created July 2009

revised May 2014