Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.
Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.
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衔接子和信号蛋白TRAF 2、TRAF 3以及cIAP 1和cIAP 2被认为通过靶向NF-κB诱导激酶（NIK）进行泛素依赖性降解，从而阻止NF-κB2前体蛋白p100的加工以释放p52，从而抑制静息细胞中的替代性核因子κ B（NF-κB）信号传导。然而，TRAF 2和TRAF 3在NIK降解和替代性NF-κB信号传导激活中的各自功能仍然是难以捉摸的。我们现在表明，CD 40或BAFF受体激活导致TRAF 3降解的cIAP 1-cIAP 2-和TRAF 2依赖性的方式，由于增强cIAP 1，cIAP 2 TRAF 3-定向泛素连接酶活性。受体诱导的cIAP 1和cIAP 2活化与TRAF 2对它们的K63连接的泛素化相关。TRAF 3的降解阻止了NIK与cIAP 1-cIAP 2-TRAF 2泛素连接酶复合物的结合，这导致NIK稳定和NF-κB2-p100加工。该通路的组成性激活导致围产期致死性和淋巴缺陷。
The adaptor and signaling proteins TRAF2, TRAF3 and cIAP1 and cIAP2 were suggested to inhibit alternative nuclear factor kappa B (NF-κB) signaling in resting cells by targeting NF-κB inducing kinase (NIK) to ubiquitin-dependent degradation, thus preventing processing of the NF-κB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-κB signaling has remained elusive. We now show that CD40 or BAFF receptor activation resulted in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2- dependent way due to enhanced cIAP1, cIAP2 TRAF3-directed ubiquitin ligase activity. Receptor-induced activation of cIAP1 and cIAP2 correlated with their K63-linked ubiquitination by TRAF2. Degradation of TRAF3 prevented association of NIK with the cIAP1-cIAP2-TRAF2 ubiquitin ligase complex, which resulted in NIK stabilization and NF-κB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.