Noncanonical NF-κB signalling. CD40 and RANK can activate the noncanonical NF-κB pathway that is dependent on NF-κB inducing kinase (NIK) expression levels. In unstimulated cells NIK forms a cytosolic complex with the ubiquitin ligases TRAF2, TRAF3 and cIAP1/2, which facilitates the K48-linked polyubiquitination and proteasomal degradation of NIK, keeping NIK levels low. Upon ligand binding, TRAF3 is recruited to the receptor, where TRAF2 directs nondegradative K63-linked polyubiquitination of cIAP1/2, resulting in their activation. Subsequently cIAP1/2 directs its K48-linked polyubiquitination to TRAF3, rather than NIK. As a result, TRAF3 is degraded and NIK is stabilised, resulting in increased NIK levels in the cell. NIK then phosphorylates and activates IKK1, which mediates NF-κB p100 phosphorylation. This is followed by K48-linked polyubiquitination and partial proteasomal degradation of p100 to p52, which forms a heterodimer with RelB to activate transcription. Next to TRAF3, TRAF1 has also been identified as a negative regulator of this pathway, most probably by competing with other TNF receptor-associated factors. cIAP, cellular inhibitor of apoptosis; IKK, IκB kinase; NF, nuclear factor; RANK, receptor activator of NF-κB; TRAF, TNF receptor-associated factor; TNF, tumour necrosis factor.
van Loo and Beyaert Arthritis Research & Therapy 2011 13:221 doi:10.1186/ar3324