TRAF2:TRAF1:cIAP1,2:TRAF3:NIK regulatory complex binds LTBR

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).<br>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).

在聚簇或二聚化后，淋巴毒素-β受体（LTBR）通过募集不同的TNF受体相关因子（TRAF）适配器至细胞质域，启动信号转导过程。LTBR通过其TRAF相互作用肽基序直接与包括TRAF2和TRAF3在内的多个TRAFs结合（参见VanArsdale等人，1997年；Nakano等人，1996年；Sanjo等人，2010年）。丝裂原活化蛋白激酶激酶激酶14（MAP3K14，亦称NIK）是非经典途径中的中心信号组分，严格调控NIK的TRAFs激活对于非经典NF-kB信号通路的有序激活至关重要。在非刺激状态下，泛素化：NIK E3连接酶复合物催化NIK的K48连接泛素化，导致NIK的持续降解。泛素化：NIK E3连接酶是一个由TRAF3和TRAF2组成的多亚基复合物，与细胞凋亡抑制因子（cIAP1,2）相关联。在激活状态下，TRAF2：cIAP1,2：TRAF3：NIK复合物在配体结合后募集至受体，随后TRAF2介导的K63连接泛素化cIAP1,2将其K48泛素化连接酶活性从NIK切换至TRAF3。由此产生的TRAF3降解导致TRAF-cIAP复合物不稳定性增加，从而允许新合成的NIK积累（参见Razani等人，2011年；Sun，2011年）。