Song H Y, Rothe M, Goeddel D V
Tularik, Inc., South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6721-5. doi: 10.1073/pnas.93.13.6721.
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-kappaB 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-kappaB. 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-kappaB activation. A20 also inhibited TNF and IL-1-induced NF-kappaB activation, suggesting that it may inhibit NF-kappaB activation signaled by diverse stimuli. The ability of A20 to block NF-kappaB 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-kappaB activation. Our findings suggest a possible molecular mechanism that could explain A20's ability to negatively regulate its own TNF-inducible expression.
TRAF1和TRAF2形成一种寡聚复合物，该复合物与肿瘤坏死因子（TNF）受体超家族各成员的胞质结构域相关联。TNF和CD40配体触发的转录因子NF-κB激活需要TRAF2发挥作用。在此我们表明，TRAF1和TRAF2与锌指蛋白A20相互作用，A20的表达由激活NF-κB的因子诱导产生。突变分析显示，A20的N端一半与TRAF1和TRAF2保守的C端TRAF结构域相互作用。在共转染实验中，A20阻断了TRAF2介导的NF-κB激活。A20还抑制了TNF和IL-1诱导的NF-κB激活，这表明它可能抑制由多种刺激信号传导的NF-κB激活。A20阻断NF-κB激活的能力定位于其C端锌指结构域。因此，A20由两个功能不同的结构域组成，一个N端TRAF结合结构域，可将A20募集到TRAF2-TRAF1复合物，另一个C端结构域介导对NF-κB激活的抑制。我们的研究结果提示了一种可能的分子机制，该机制可以解释A20负向调节其自身TNF诱导表达的能力。
