Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-κB activation
Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-κB activation
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DOI：
10.1074/jbc.m310969200
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发表时间：
2004-01-02
影响因子：
4.8
通讯作者：
Wajant, H
中科院分区：
文献类型：
--
作者：
Fotin-Mleczek, M;Henkler, F;Wajant, H
为了研究活细胞中CD 40信号复合物的形成，我们使用绿色荧光蛋白（GFP）标记的CD 40信号中间体和共聚焦生命成像。大多数细胞质TRAF 2-GFP和较小程度的TRAF 3-GFP，但TRAF 1-GFP或TRAF 4-GFP，在CD 40与CD 40配体触发后几分钟内易位到CD 40信号传导复合物中。凋亡抑制蛋白cIAP 1和cIAP 2也被TRAF 2募集到CD 40信号传导位点。过量的TRAF 2允许TRAF 1-GFP募集到CD 40信号传导的位点，而过量的TRAF 1废除TRAF 2和CD 40的相互作用。然而，TRAF 1的过表达对TRADD和TRAF 2的相互作用没有影响，而TRADD和TRAF 2对肿瘤坏死因子受体1（TNF-R1）介导的NF-κ B活化很重要。因此，TRAF 1抑制CD 40依赖性但不抑制TNF-R1依赖性NF-κ B活化。此外，用小干扰RNA下调TRAF 1增强了CD 40/CD 40配体诱导的NF-κ B活化，但对TNF信号传导没有影响。由于TRAF蛋白的三聚体结构，我们认为TRAF 1-TRAF 2异聚体复合物（（TRAF 2）（2）-TRAF 1与TRAF 2-（TRAF 1）（2））的化学计量决定了它们介导CD 40信号传导的能力，但对TNF信号传导没有重大影响。
To investigate CD40 signaling complex formation in living cells, we used green fluorescent protein (GFP)tagged CD40 signaling intermediates and confocal life imaging. The majority of cytoplasmic TRAF2-GFP and, to a lesser extent, TRAF3-GFP, but not TRAF1-GFP or TRAF4-GFP, translocated into CD40 signaling complexes within a few minutes after CD40 triggering with the CD40 ligand. The inhibitor of apoptosis proteins cIAP1 and cIAP2 were also recruited by TRAF2 to sites of CD40 signaling. An excess of TRAF2 allowed recruitment of TRAF1-GFP to sites of CD40 signaling, whereas an excess of TRAF1 abrogated the interaction of TRAF2 and CD40. Overexpression of TRAF1, however, had no effect on the interaction of TRADD and TRAF2, known to be important for tumor necrosis factor receptor 1 (TNF-R1)-mediated NF-kappaB activation. Accordingly, TRAF1 inhibited CD40-dependent but not TNF-R1-dependent NF-kappaB activation. Moreover, down-regulation of TRAF1 with small interfering RNAs enhanced CD40/ CD40 ligand-induced NF-kappaB activation but showed no effect on TNF signaling. Because of the trimeric organization of TRAF proteins, we propose that the stoichiometry of TRAF1-TRAF2 heteromeric complexes (( TRAF2)(2)-TRAF1 versus TRAF2-(TRAF1)(2)) determines their capability to mediate CD40 signaling but has no major effect on TNF signaling.