Liao Gongxian, Zhang Minying, Harhaj Edward W, Sun Shao-Cong
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
J Biol Chem. 2004 Jun 18;279(25):26243-50. doi: 10.1074/jbc.M403286200. Epub 2004 Apr 14.
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.
转录因子NF-κB家族在多种生物学过程的调控中发挥着关键作用，这些过程包括免疫反应、细胞生长和细胞凋亡。NF-κB的激活由经典和非经典信号通路介导。尽管经典通路已得到广泛研究，但介导非经典通路的机制仍知之甚少。最近的研究已确定NF-κB诱导激酶（NIK）是非经典NF-κB激活通路的关键组成部分；然而，NIK的信号功能如何被调控仍然未知。我们在此报告，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发生物理结合；这种分子相互作用似乎使NIK被蛋白酶体降解。有趣的是，细胞外信号诱导非经典NF-κB信号涉及TRAF3的降解以及NIK表达的相应增强。这些结果表明，非经典NF-κB信号的诱导可能涉及NIK从TRAF3介导的负调控中被拯救出来。
