TRAF3:NIK binds TRAF2:cIAP1/2

Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway which integrates signals from TNFR2 and activates IkB kinase-alpha (IkBA) for triggering p100 phosphorylation and processing (Sun 2011). A tight control of NIK stability is essential to achieve controlled activation of the noncanonical NF-kB signalling upon TNFR2 activation. In unstimulated cells the level of NIK protein is extremely low, which is due to constant degradation by a ubiquitination-dependent mechanism (Liao et al. 2004). Proteasomal degradation of NIK occurs on assembly of a regulatory complex through TRAF3 complexed with NIK and TRAF2 which exists in a preassembled complex with cellular Inhibitor of apoptosis 1 (cIAP1) and cIAP2 (cIAP1,2:TRAF2::TRAF3:NIK). The c-IAPs do not directly contact TNFR2, but rather associate with TRAF2 through their N-terminal BIR motif-comprising domain (Rothe et al. 1995, Shu et al. 1996). TRAF3 functions as a bridging factor between cIAP1/2-TRAF2 E3 complex and NIK enabling cIAP to mediate K48 linked ubiquitination of NIK (Zarnegar et al. 2008, Vallabhapurapu et al. 2008, Li et al. 2004).

丝裂原活化蛋白激酶激酶激酶14（MAP3K14，亦称NIK）系非经典信号通路的核心组成部分，该通路整合TNFR2的信号并激活IkB激酶-α（IkBA），以启动p100的磷酸化和加工（Sun，2011）。NIK稳定性的严格调控对于在TNFR2激活后实现对非经典NF-kB信号通路的有序激活至关重要。在非刺激细胞中，NIK蛋白的水平极为低下，这归因于持续的泛素化依赖性降解机制（Liao等，2004）。NIK的蛋白酶体降解发生在调节复合物的组装过程中，该复合物由与NIK结合的TRAF3和存在于与细胞凋亡抑制因子1（cIAP1）和cIAP2（cIAP1,2:TRAF2::TRAF3:NIK）预组装复合物中的TRAF2构成。c-IAPs并不直接与TNFR2接触，而是通过其N端BIR基序构成的域与TRAF2相联系（Rothe等，1995，Shu等，1996）。TRAF3作为cIAP1/2-TRAF2 E3复合物与NIK之间的桥梁因子，使cIAP能够介导NIK的K48连接泛素化（Zarnegar等，2008，Vallabhapurapu等，2008，Li等，2004）。