Canonical and alternative pathway of NF-κB activation. (A) Activation of the canonical NF-κB pathway. A series of stimuli activate the canonical pathway of NF-κB activation, including proinflammatory cytokines such as IL-1, TNF-α, or pathogen-associated molecular patterns that bind to TLRs, the antigen receptors TCR/BCR, or lymphocyte coreceptors such as CD40, CD30, or receptor activator of NF-κB (RANK) (1). Activated IKK phosphorylates IκB proteins on 2 conserved serine residues and induces IκB polyubiquitinylation (2), which in turn induces their recognition by the proteasome and causes successive proteolytic degradation (3). Following the IκB degradation, the cytoplasmic NF-κB dimers are released and translocate into the nucleus, where gene transcription is activated (4). (B) Activation of the alternative NF-κB pathway. The alternative pathway of NF-κB activation is engaged by a restricted set of cell-surface receptors that belong to the TNF receptor superfamily, including CD40, the lymphotoxin β receptor, and the BAFF receptor (a). This pathway culminates in the activation of IKKα (b), which can directly phosphorylate NF-κB2/p100 (c), inducing partial proteolysis of p100 to p52 by the proteasome (d). The p52 protein lacks the inhibitory ankyrin repeats and preferentially dimerizes with RelB to translocate into the nucleus (e). Illustration by Kenneth Probst.