Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation
Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation
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DOI：
10.1038/emboj.2012.241
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发表时间：
2012-10-03
期刊：
影响因子：
11.4
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Tokunaga, Fuminori;Nishimasu, Hiroshi;Nureki, Osamu
LUBAC（线性泛素链组装复合物）通过NEMO（NF-κ B必需调节剂，也称为IKK γ）和RIP 1的线性多泛素化激活经典NF-κ B途径。然而，LUBAC介导的NF-κ B激活的调节机制仍然是难以捉摸的。在这里，我们发现，A20抑制LUBAC介导的NF-κ B B的激活，通过C-末端第七锌指（ZF 7）结合线性多聚泛素，而CYLD抑制它通过去泛素化酶（DU B）的活动。我们在1.70-1.98埃分辨率下确定了与线性双泛素复合的A20 ZF 7的晶体结构。晶体结构显示A20 ZF 7同时识别Met 1连接的近端和远端泛素，并且与B细胞淋巴瘤相关的基因突变映射到泛素结合位点。我们的功能分析表明，A20 ZF 7与线性多聚泛素的结合有助于A20募集到含有LUBAC和I κ B激酶（IKK）的TNF受体（TNFR）信号传导复合物中，这导致NF-κ B抑制。这些发现为免疫和炎症反应的调节提供了新的见解。The EMBO Journal（2012）31，3856-3870. doi：10.1038/daj.2012.241; 2012年8月28日在线发布
LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-kappa B pathway through linear polyubiquitination of NEMO (NF-kappa B essential modulator, also known as IKK gamma) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-kappa B activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-kappa B activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 angstrom resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and I kappa B kinase (IKK), which results in NF-kappa B suppression. These findings provide new insight into the regulation of immune and inflammatory responses. The EMBO Journal (2012) 31, 3856-3870. doi:10.1038/emboj.2012.241; Published online 28 August 2012