Structure-function analysis of the A20-binding inhibitor of NF-κB activation, ABIN-1
Structure-function analysis of the A20-binding inhibitor of NF-κB activation, ABIN-1
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DOI：
10.1016/s0014-5793(03)00041-3
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发表时间：
2003-02-11
期刊：
影响因子：
3.5
通讯作者：
Beyaert, R
中科院分区：
文献类型：
--
作者：
Heyninck, K;Kreike, MM;Beyaert, R
核因子κ B（NF-κ B）依赖性基因表达在许多细胞过程中起重要作用，包括应激反应、炎症和细胞增殖。因此，这种转录因子的活性需要严格调控。其中，NF-κ B依赖性锌指蛋白A20参与响应于肿瘤坏死因子（TNF）的NF-κ B活化的负反馈调节。我们先前证明A20可以与A20结合的NF-κ B激活抑制剂（ABIN）相互作用，ABIN具有抑制TNF诱导的NF-κ B过表达激活的潜力。因此，ABIN蛋白被认为介导A20的NF-κ B抑制功能。在这里，我们证明了存在一个短的同源区域的ABIN和IkappaB激酶γ，调节亚基的IkappaB激酶复合物。该区域的位点特异性突变消除了ABIN-1的NF-κ B抑制功能，而不影响与A20的相互作用。此外，这些ABIN-1突变体的共表达以显性负性方式干扰ABIN-1的NF-κ B抑制功能，而A20介导的抑制不受影响。这些结果表明，A20和ABIN-I可能独立于它们的相互作用而起作用。(C)2003年由Elsevier Science B. V.代表欧洲生物化学学会联合会出版。
Nuclear factor kappaB (NF-kappaB)-dependent gene expression plays an important role in numerous cellular processes including stress responses, inflammation and cell proliferation. Therefore, the activity of this transcription factor needs to be tightly regulated. Among others, the NF-kappaB-dependent zinc finger protein A20 is involved in the negative feedback regulation of NF-kappaB activation in response to tumor necrosis factor (TNF). We previously demonstrated that A20 can interact with A20-binding inhibitors of NF-kappaB activation (ABINs), which have the potential to inhibit TNF-induced activation of NF-kappaB upon overexpression. The ABIN proteins were therefore propose to mediate the NF-kappaB inhibiting function of A20. Here we demonstrate the presence of a short homologous region in ABINs and IkappaB kinase gamma, the regulatory subunit of the IkappaB kinase complex. Site-specific mutagenesis of this region abolished the NF-kappaB inhibiting function of ABIN-1, without affecting the interaction with A20. Furthermore, coexpression of these ABIN-1 mutants interfered in a dominant negative manner with the NF-kappaB inhibiting function of ABIN-1, whereas the A20-mediated inhibition was unaffected. These results suggest that A20 and ABIN-I probably act independently of their mutual interaction. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.