De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling
De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling
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DOI：
10.1038/nature02794
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发表时间：
2004-08-05
期刊：
影响因子：
64.8
通讯作者：
Dixit, VM
中科院分区：
文献类型：
--
作者：
Wertz, IE;O'Rourke, KM;Dixit, VM
NF-kappaB 转录因子介导肿瘤坏死因子-α 和白介素-1β(1) 等促炎细胞因子的作用。正如在 A20 缺陷小鼠中观察到的那样，未能下调 NF-kappaB 转录活性会导致慢性炎症和细胞死亡 (2)。 A20 是 NF-kappaB 信号传导的有效抑制剂，但其作用机制尚不清楚(2)。在这里，我们表明 A20 通过其两个泛素编辑域的协同活动下调 NF-kappaB 信号传导。 A20 的氨基末端结构域是 OTU（卵巢肿瘤）家族的一种去泛素化 (DUB) 酶 (3)，它可从受体相互作用蛋白 (RIP) 中去除赖氨酸 63 (K63) 连接的泛素链，RIP 是近端 TNF 受体 1 (TNFR1) 信号复合物的重要介质 (4,5)。 A20 的羧基末端结构域由 7 个 C-2/C-2 锌指 (6) 组成，然后通过用 K48 连接的泛素链对 RIP 进行多泛素化，充当泛素连接酶，从而靶向 RIP 进行蛋白酶体降解。在这里，我们定义了一个新的泛素连接酶结构域，并确定了 A20 下调 NF-kappaB 信号传导的两种连续机制。我们还提供了一个含有单独的泛素连接酶和 DUB 结构域的蛋白质的例子，这两个结构域都参与介导不同的调节作用。
NF-kappaB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta(1). Failure to downregulate NF-kappaB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice(2). A20 is a potent inhibitor of NF-kappaB signalling, but its mechanism of action is unknown(2). Here we show that A20 downregulates NF-kappaB signalling through the cooperative activity of its two ubiquitin-editing domains. The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family(3), removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein ( RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex(4,5). The carboxy-terminal domain of A20, composed of seven C-2/C-2 zinc fingers(6), then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Here we define a novel ubiquitin ligase domain and identify two sequential mechanisms by which A20 downregulates NF-kappaB signalling. We also provide an example of a protein containing separate ubiquitin ligase and DUB domains, both of which participate in mediating a distinct regulatory effect.