The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappa B activation
The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappa B activation
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DOI：
10.1073/pnas.93.13.6721
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发表时间：
1996-06-25
影响因子：
11.1
通讯作者：
Goeddel, DV
中科院分区：
文献类型：
--
作者：
Song, HY;Rothe, M;Goeddel, DV
TRAF 1和TRAF 2形成与肿瘤坏死因子（TNF）受体超家族的各种成员的胞质结构域缔合的寡聚复合物。TRAF 2的作用是激活由TNF和CD 40配体触发的转录因子NF-κ B所必需的。在这里，我们表明TRAF 1和TRAF 2与A20相互作用，A20是一种锌指蛋白，其表达由激活NF-κ B的试剂诱导。突变分析显示，A20的N-末端一半与TRAF 1和TRAF 2的保守C-末端TRAF结构域相互作用。在共转染实验中，A20阻断TRAF 2介导的NF-κ B活化。A20还抑制TNF和IL-1诱导的NF-κ B激活，这表明它可能抑制由不同刺激信号发出的NF-κ B激活。A20阻断NF-κ B激活的能力被映射到其C末端锌指结构域。因此，A20由两个功能不同的结构域组成，N-末端TRAF结合结构域将A20募集至TRAF 2-TRAF 1复合物，C-末端结构域介导NF-κ B活化的抑制。我们的研究结果提示了一种可能的分子机制，可以解释A20负调节其自身TNF诱导表达的能力。
TRAF1 and TRAF2 form an oligomeric complex that associates with the cytoplasmic domains of various members of the tumor necrosis factor (TNF) receptor superfamily. TRAF2 action is required for activation of the transcription factor NF-kappa B triggered by TNF and the CD40 ligand. Here we show that TRAF1 and TRAF2 interact with A20, a zinc finger protein, whose expression is induced by agents that activate NF-kappa B. Mutational analysis revealed that the N-terminal half of A20 interacts with the conserved C-terminal TRAF domain of TRAF1 and TRAF2. In cotransfection experiments, A20 blocked TRAF2-mediated NF-kappa B activation. A20 also inhibited TNF and IL-1-induced NF-kappa B activation, suggesting that it may inhibit NF-kappa B activation signaled by diverse stimuli, The ability of A20 to block NF-kappa B activation was mapped to its C-terminal zinc finger domain. Thus, A20 is composed of two functionally distinct domains, an N-terminal TRAF binding domain that recruits A20 to the TRAF2-TRAF1 complex and a C-terminal domain that mediates inhibition of NF-kappa B activation. Our findings suggest a Possible molecular mechanism that could explain A20's ability to negatively regulate its own TNF inducible expression.