APPL1 regulates basal NF-κB activity by stabilizing NIK.
APPL1 regulates basal NF-κB activity by stabilizing NIK.
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DOI：
10.1242/jcs.105171
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发表时间：
2012-09-01
影响因子：
4
通讯作者：
Miaczynska M
中科院分区：
文献类型：
--
作者：
Hupalowska A;Pyrzynska B;Miaczynska M
APPL 1是结合膜受体、信号蛋白和核因子的多功能衔接蛋白，从而在内体运输和不同的信号通路中起作用。在此，我们发现APPL 1在基础条件下而非TNFα刺激条件下作为NF-κB转录活性的正调节因子的新作用。APPL 1被发现与TRAF 2直接相互作用，TRAF 2是一种已知激活经典NF-κB信号传导的衔接蛋白。APPL 1与TRAF 2协同诱导NF-κB活化，这两种蛋白质都是该过程所必需的，并且在IKK复合物的上游起作用。虽然TRAF 2在APPL内体上检测不到，但APPL 1的内体募集是其在NF-κB通路中发挥功能所必需的。重要的是，在经典途径中，APPL 1似乎在没有细胞因子刺激的情况下调节NF-κB的p65亚基的适当空间分布，因为其过表达增强而其缺失减少了p65的核积聚。通过分析APPL 1过量产生或缺失时的基因转录模式，我们发现编码细胞因子的NF-κB靶基因的表达改变。在分子水平上，过表达的APPL 1通过减少NIK与含有TRAF 2、TRAF 3和cIAP 1的降解复合物的结合，显著增加了NIK的水平，NIK是非经典NF-κB途径的关键组分。反过来，高水平的NIK触发了p65的核转位。总的来说，我们认为APPL 1通过调节NIK的稳定性来调节基础NF-κB活性，从而影响p65的活化。这使得APPL 1成为NF-κB激活的经典机制和非经典机制之间的一个新的联系。
APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under basal but not TNFα-stimulated conditions. APPL1 was found to directly interact with TRAF2, an adaptor protein known to activate canonical NF-κB signaling. APPL1 synergized with TRAF2 to induce NF-κB activation, and both proteins were necessary for this process and function upstream of the IKK complex. Although TRAF2 was not detectable on APPL endosomes, endosomal recruitment of APPL1 was required for its function in the NF-κB pathway. Importantly, in the canonical pathway, APPL1 appeared to regulate the proper spatial distribution of the p65 subunit of NF-κB in the absence of cytokine stimulation, since its overexpression enhanced and its depletion reduced the nuclear accumulation of p65. By analyzing the patterns of gene transcription upon APPL1 overproduction or depletion we found altered expression of NF-κB target genes that encode cytokines. At the molecular level, overexpressed APPL1 markedly increased the level of NIK, the key component of the noncanonical NF-κB pathway, by reducing its association with the degradative complex containing TRAF2, TRAF3 and cIAP1. In turn, high levels of NIK triggered nuclear translocation of p65. Collectively, we propose that APPL1 regulates basal NF-κB activity by modulating the stability of NIK, which affects the activation of p65. This places APPL1 as a novel link between the canonical and noncanonical machineries of NF-κB activation.
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