Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology
Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology
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DOI：
10.1093/hmg/ddq222
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发表时间：
2010-08-15
影响因子：
3.5
通讯作者：
Courtois, Gilles
中科院分区：
文献类型：
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作者：
Gautheron, Jeremie;Pescatore, Alessandra;Courtois, Gilles
NF-kappa B必需调节剂（NEMO）作为I -kappa B激酶的调控亚基，在NF-kappa B活化中起关键作用。在细胞受到刺激后，NEMO可以通过磷酸化、聚合化或泛素化进行修饰。在后一种情况下，对于这种翻译后修饰的确切功能所知不多。TRAF6是导致k63连锁NEMO多泛素化的E3连接酶之一，它参与控制免疫、破骨细胞发生、皮肤发育和脑功能的几个信号通路。我们之前观察到NEMO和TRAF6之间潜在的重要相互作用。在这项研究中，我们更详细地定义了这种相互作用所需的结构域，发现了位于NEMO氨基末端的TRAF6的新结合位点，并被TRAF6的卷曲结构域识别。该位点似乎与先前发现的NEMO泛素结合域协同工作，该泛素结合域结合多泛素化链，表明TRAF6识别的双重模式。我们还发现，在轻度遗传性疾病色素失禁中发现NEMO的E57K突变，导致TRAF6结合和IL-1 β信号通路受损。相反，tnf - α对nf - κ B的激活不受影响。这些数据表明NEMO/TRAF6相互作用具有生理相关性，可能代表治疗目的的新靶点。
NF-kappa B Essential MOdulator (NEMO) has been shown to play a critical role in NF-kappa B activation, as the regulatory subunit of I kappa B kinase. Upon cell stimulation, NEMO can be modified through phosphorylation, sumoylation or ubiquitination. In the latter case, not much is known regarding the exact function of this posttranslational modification. One of the E3 ligase responsible for K63-linked NEMO polyubiquitination is TRAF6, which participates in several signaling pathways controlling immunity, osteoclastogenesis, skin development and brain functions. We previously observed a potentially important interaction between NEMO and TRAF6. In this study, we defined in more detail the domains required for this interaction, uncovering a new binding site for TRAF6 located at the amino-terminus of NEMO and recognized by the coiled-coil domain of TRAF6. This site appears to work in concert with the previously identified NEMO ubiquitin-binding domain which binds polyubiquitinated chains, suggesting a dual mode of TRAF6 recognition. We also showed that E57K mutation of NEMO found in a mild form of the genetic disease incontinentia pigmenti, resulted in impaired TRAF6 binding and IL-1 beta signaling. In contrast, activation of NF-kappa B by TNF-alpha was not affected. These data demonstrate that NEMO/TRAF6 interaction has physiological relevance and might represent a new target for therapeutic purposes.