Shembade Noula, Harhaj Nicole S, Liebl Daniel J, Harhaj Edward W
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL 33136, USA.
EMBO J. 2007 Sep 5;26(17):3910-22. doi: 10.1038/sj.emboj.7601823. Epub 2007 Aug 16.
The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.
核因子-κB（NF-κB）转录因子通常由促炎细胞因子和细菌脂多糖（LPS）短暂激活；然而，在炎症性疾病和恶性肿瘤中通常可观察到NF-κB的持续激活。泛素编辑酶A20通过使关键信号分子失活，在肿瘤坏死因子-α（TNF-α）和LPS介导的NF-κB信号传导的终止中发挥重要作用。然而，关于A20如何被调控以及其他分子是否在NF-κB信号传导的终止中发挥作用，我们知之甚少。在此我们证明，Tax1结合蛋白1（TAX1BP1）对于响应TNF-α、白细胞介素-1（IL-1）和LPS刺激时NF-κB和应激活化蛋白激酶（JNK）激活的终止至关重要。在缺乏TAX1BP1的小鼠成纤维细胞中，由于受体相互作用蛋白1（RIP1）和肿瘤坏死因子受体相关因子6（TRAF6）的泛素化增强，TNF-α、IL-1和LPS介导的IκB激酶（IKK）和JNK激活升高且持续。此外，在缺乏TAX1BP1的情况下，A20在RIP1结合、TRAF6的去泛素化以及NF-κB激活的抑制方面受损。因此，TAX1BP1通过作为A20的关键调节因子，在NF-κB和JNK信号传导的终止中起关键作用。
