Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation
Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation
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DOI：
10.1074/jbc.m403286200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Sun, SC
中科院分区：
文献类型：
--
作者：
Liao, GX;Zhang, MY;Sun, SC
NF-kappaB转录因子家族在多种生物过程的调控中起着关键作用，包括免疫应答、细胞生长和细胞凋亡。NF-kappaB的激活是由典型和非典型信号通路介导的。尽管规范途径已被广泛研究，但介导非规范途径的机制仍知之甚少。最近的研究已经确定NF-kappaB诱导激酶（NIK）是NF-kappaB非典型激活途径的关键组成部分；然而，NIK的信号功能是如何调控的仍然未知。我们在此报道，NIK调控的一个重要机制是通过其与肿瘤坏死因子受体相关因子3 （TRAF3）的动态相互作用。TRAF3通过位于NIK n端区域的特定序列基序与NIK物理关联；这种分子相互作用似乎以蛋白酶体降解NIK为目标。有趣的是，细胞外信号诱导非规范NF-kappaB信号转导涉及TRAF3的降解和伴随的NIK表达增强。这些结果表明，非规范NF-kappaB信号的诱导可能涉及将NIK从traf3介导的负调控中拯救出来。
The NF-kappaB family of transcription factors plays a pivotal role in regulation of diverse biological processes, including immune responses, cell growth, and apoptosis. Activation of NF-kappaB is mediated by both canonical and noncanonical signaling pathways. Although the canonical pathway has been extensively studied, the mechanism mediating the noncanonical pathway is still poorly understood. Recent studies have identified the NF-kappaB-inducing kinase (NIK) as a key component of the noncanonical pathway of NF-kappaB activation; however, how the signaling function of NIK is regulated remains unknown. We report here that one important mechanism of NIK regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (TRAF3). TRAF3 physically associates with NIK via a specific sequence motif located in the N-terminal region of NIK; this molecular interaction appears to target NIK for degradation by the proteasome. Interestingly, induction of noncanonical NF-kappaB signaling by extracellular signals involves degradation of TRAF3 and the concomitant enhancement of NIK expression. These results suggest that induction of noncanonical NF-kappaB signaling may involve the rescue of NIK from TRAF3-mediated negative regulation.