ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB
ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB
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DOI：
10.1074/jbc.m601502200
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发表时间：
2006-07-07
影响因子：
4.8
通讯作者：
Leonardi, Antonio
中科院分区：
文献类型：
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作者：
Mauro, Claudio;Pacifico, Francesco;Leonardi, Antonio
核因子-κ B（NF-κ B）在炎症、免疫、应激反应和保护免于细胞凋亡中起关键作用。NF-κ B的典型活化依赖于抑制性亚基I κ B α的磷酸化，其由称为I κ B激酶（IKK）复合物的多聚体高分子量复合物介导。它由两个催化亚基（IKK α和IKK β）和一个调节亚基（NEMO/IKK γ）组成。后一种蛋白对于IKK和NF-κ B的活化是必需的，但其作用机制尚不清楚。在这里，我们确定ABIN-1（NF-κ B的A20结合抑制剂）作为NEMO/IKK γ相互作用蛋白。ABIN-1先前已被鉴定为A20结合蛋白，并且已提出其介导A20的NF-κ B抑制作用。我们发现ABIN-1和A20都在IKK复合物水平抑制NF-κ B，A20通过NEMO/IKK γ的去泛素化抑制NF-κ B的活化。重要的是，靶向ABIN-1的小干扰RNA消除了NEMO/IKK γ的A20依赖性去泛素化，并且A20的RNA干扰损害了ABIN-1抑制NF-κ B活化的能力。总之，我们的数据表明，ABIN-1物理连接A20到NEMO/IKK γ，并促进A20介导的NEMO/IKK γ的去泛素化，从而导致NF-κ B的抑制。
Nuclear factor kappa B (NF-kappa B) plays a pivotal role in inflammation, immunity, stress responses, and protection from apoptosis. Canonical activation of NF-kappa B is dependent on the phosphorylation of the inhibitory subunit I kappa B alpha that is mediated by a multimeric, high molecular weight complex, called I kappa B kinase (IKK) complex. This is composed of two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, NEMO/IKK gamma. The latter protein is essential for the activation of IKKs and NF-kappa B, but its mechanism of action is not well understood. Here we identified ABIN-1 (A20 binding inhibitor of NF-kappa B) as a NEMO/IKK gamma-interacting protein. ABIN-1 has been previously identified as an A20-binding protein and it has been proposed to mediate the NF-kappa B inhibiting effects of A20. We find that both ABIN-1 and A20 inhibit NF-kappa B at the level of the IKK complex and that A20 inhibits activation of NF-kappa B by de-ubiquitination of NEMO/IKK gamma. Importantly, small interfering RNA targeting ABIN-1 abrogates A20-dependent de-ubiquitination of NEMO/IKK gamma and RNA interference of A20 impairs the ability of ABIN-1 to inhibit NF-kappa B activation. Altogether our data indicate that ABIN-1 physically links A20 to NEMO/IKK gamma and facilitates A20-mediated de-ubiquitination of NEMO/IKK gamma, thus resulting in inhibition of NF-kappa B.