After clustering or dimerisation lymphotoxin-beta receptor (LTBR) initiates signal transduction by recruiting different TNF receptor-associated factor (TRAF) adaptors to the cytoplasmic domain. LTBR directly binds to several TRAFs, including TRAF2 and TRAF3 through its TRAF-interacting peptide motif (VanArsdale et al. 1997, Nakano et al. 1996, Sanjo et al. 2010).
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway and a tight control of NIK activation by TRAFs is essential to achieve controlled activation of the noncanonical NF-kB signalling. In unstimulated cells ubiquitin:NIK E3 ligase complex catalyses K48-linked ubiquitination of NIK, leading to constitutive NIK degradation. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with cellular inhibitors of apoptosis (cIAP1,2). In the activated state the TRAF2:cIAP1,2:TRAF3:NIK complex is recruited to the receptor upon ligand binding whereupon TRAF2-mediated, K63-linked ubiquitination of cIAP1,2 switches its K48 ubiquitin ligase activity from NIK to TRAF3. The resultant TRAF3 degradation destabilizes the TRAF-cIAP complex, so allowing the accumulation of newly synthesised NIK (Razani et al. 2011, Sun 2011).