Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].
Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].
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DOI：
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发表时间：
2006
影响因子：
21.3
通讯作者：
Chuan-Jin Wu;D. Conze;Tao Li;S. Srinivasula;J. Ashwell
中科院分区：
文献类型：
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作者：
Chuan-Jin Wu;D. Conze;Tao Li;S. Srinivasula;J. Ashwell
转录因子NF-kappaB与IkappaB形成复合体，隔离在细胞质中。几乎所有的核因子-kappaB激活途径都汇聚在IkappaB激酶(IKK)上，它使IkappaB磷酸化，导致Lys 48连接的IkappaB的多泛素化及其降解。这允许核因子-kappaB迁移到细胞核，在那里它调节基因的表达。IKK有两个催化亚基IKKalpha和IKKbeta，以及一个调节亚单位IKKGamma或Nemo。NEMO是核因子-kappaB激活所必需的，人类NEMO功能障碍是导致色素性失禁和少汗性外胚层发育不良及免疫缺陷(Hed-ID)的原因。IKK在被占据的细胞因子受体上的募集和随后的激活依赖于Lys 63连接的多泛素链与受体相互作用蛋白(RIP)等信号中间体的连接。在这里，我们发现Nemo与Lys 63-而不是Lys 48-连接的多泛素结合，并且Nemo的单点突变阻止了与Lys 63-连接的多泛素的结合，也取消了在肿瘤坏死因子(TNF)-α刺激的细胞中Nemo与RIP的结合，IKK与肿瘤坏死因子受体(TNF-R)1的募集，以及IKK和NF-kappaB的激活。在没有NEMO结合的情况下，RIP也是不稳定的，并在肿瘤坏死因子-α处理的细胞中经历蛋白酶体的降解。这些结果为NEMO在IKK激活中的关键作用提供了机制，也为理解细胞因子受体近端信号与IKK和NF-kappaB激活之间的联系提供了关键。
The transcription factor NF-kappaB is sequestered in the cytoplasm in a complex with IkappaB. Almost all NF-kappaB activation pathways converge on IkappaB kinase (IKK), which phosphorylates IkappaB resulting in Lys 48-linked polyubiquitination of IkappaB and its degradation. This allows migration of NF-kappaB to the nucleus where it regulates gene expression. IKK has two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma or NEMO. NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). The recruitment of IKK to occupied cytokine receptors, and its subsequent activation, are dependent on the attachment of Lys 63-linked polyubiquitin chains to signalling intermediates such as receptor-interacting protein (RIP). Here, we show that NEMO binds to Lys 63- but not Lys 48-linked polyubiquitin, and that single point mutations in NEMO that prevent binding to Lys 63-linked polyubiquitin also abrogates the binding of NEMO to RIP in tumour necrosis factor (TNF)-alpha-stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-kappaB. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells. These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation.