TRAF2和TRAF3在激活NIK依赖的替代性NF-κB信号传导的泛素化级联反应中的非冗余和互补功能。
Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.
作者信息
Vallabhapurapu Sivakumar, Matsuzawa Atsushi, Zhang Weizhou, Tseng Ping-Hui, Keats Jonathan J, Wang Haopeng, Vignali Dario A A, Bergsagel P Leif, Karin Michael
机构信息
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Cancer Center, University of California, San Diego, California 93093, USA.
出版信息
Nat Immunol. 2008 Dec;9(12):1364-70. doi: 10.1038/ni.1678. Epub 2008 Nov 9.
The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-kappaB (NF-kappaB) signaling in resting cells by targeting NF-kappaB-inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-kappaB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-kappaB signaling have remained elusive. We now show that CD40 or BAFF receptor activation result in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2-dependent way owing 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-kappaB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.
衔接蛋白和信号蛋白TRAF2、TRAF3、cIAP1和cIAP2可能通过将核因子-κB诱导激酶（NIK）靶向泛素依赖性降解，从而在静息细胞中抑制替代性核因子-κB（NF-κB）信号传导，进而阻止NF-κB2前体蛋白p100加工释放p52。然而，TRAF2和TRAF3在NIK降解及替代性NF-κB信号激活中的各自功能仍不清楚。我们现在表明，CD40或BAFF受体激活以cIAP1-cIAP2和TRAF2依赖性方式导致TRAF3降解，这是由于cIAP增强了1、cIAP2介导的TRAF3泛素连接酶活性。受体诱导的cIAP1和cIAP2激活与其被TRAF2进行K63连接的泛素化相关。TRAF3的降解阻止了NIK与cIAP1-cIAP2-TRAF2泛素连接酶复合物的结合，这导致NIK稳定和NF-κB2-p100加工。该信号通路的组成性激活会导致围产期致死和淋巴缺陷。
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