Figure 4

Noncanonical activation of NFκB. NFκB-inducing kinase (NIK) activates the noncanonical pathway of NFκB. In resting cells, NIK is ubiquitinated by a ubiquitin-ligase complex, composed of TRAF3-TRAF2-cIAP1 and/or cIAP2, and is proteasomally degraded. Stimulation of the receptor by a ligand of the TNF receptor (TNFR) family, such as CD40, B-cell activating factor, receptor lymphotoxin-α, receptor activator for NFκB and TNFR2, leads to recruitment of the TRAF3-TRAF2-cIAP complex to the receptor. TRAF3 is ubiquitinated in a cIAP-dependent manner and further degraded by the proteasome. This loss of TRAF3 prevents binding of NIK to the ubiquitin-ligase complex. NIK can escape from ubiquitination and subsequent degradation resulting in accumulation in the cytosol. This allows NIK to activate inhibitor of NFκB kinases a (IKKα) by phosphorylating serine 176 and serine 180. Subsequently, IKKα phosphorylates NFKB2. This allows ubiquitination and partial degradation of NFκB2 to p52. The C-terminal ankyrin repeats of NFκB2 are degraded. This allows NFκB2 to form dimers with RelB and to translocate to the nucleus. The noncanonical pathway can be activated by members of the TNF receptor superfamily. CIAP, cellular inhibitors of apoptosis; E2, estradiol; P, phosphogroup; TRAF, TNF receptor-associated factor; Ub, ubiquitin.