State Key Laboratory of Biocontrol, Department of Biochemistry, College of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.
Proc Natl Acad Sci U S A. 2014 May 6;111(18):6720-5. doi: 10.1073/pnas.1321187111. Epub 2014 Apr 21.
In the past decade, ubiquitination has been well documented to have multifaceted roles in regulating NF-κB activation in mammals. However, its function, especially how deubiquitinating enzymes balance the NF-κB activation, remains largely elusive in invertebrates. Investigating bbtA20 and its binding proteins, bbt A20-binding inhibitor of NF-κB (bbtABIN1) and bbtABIN2, in Chinese amphioxus Branchiostoma belcheri tsingtauense, we found that bbtABIN2 can colocalize and compete with bbt TNF receptor-associated factor 6 to connect the K63-linked polyubiquitin chains, whereas bbtABIN1 physically links bbtA20 to bbt NF-κB essential modulator (bbtNEMO) to facilitate the K48-linked ubiquitination of bbtNEMO. Similar to human A20, bbtA20 is a dual enzyme that removes the K63-linked polyubiquitin chains and builds the K48-linked polyubiquitin chains on bbt receptor-interacting serine/threonine protein kinase 1b, leading to the inhibition of NF-κB signaling. Our study not only suggests that ubiquitination is an ancient strategy in regulating NF-κB activation but also provides the first evidence, to our knowledge, for ABINs/A20-mediated inhibition of NF-κB via modifying the ubiquitinated proteins in a basal chordate, adding information on the stepwise development of vertebrate innate immune signaling.
在过去的十年中,泛素化在调节哺乳动物 NF-κB 激活方面的多方面作用已得到充分证实。然而,泛素化在无脊椎动物中如何发挥作用,特别是去泛素化酶如何平衡 NF-κB 的激活,在很大程度上仍然难以捉摸。本研究以中国青岛文昌鱼(Branchiostoma belcheri tsingtauense)为模型,研究 bbtA20 及其结合蛋白 bbt A20 结合的 NF-κB 抑制剂(bbtABIN1 和 bbtABIN2),发现 bbtABIN2 可以与 bbt TNF 受体相关因子 6 共定位并竞争,连接 K63 连接的多泛素链,而 bbtABIN1 将 bbtA20 与 bbt NF-κB 必需调节剂(bbtNEMO)物理连接,促进 bbtNEMO 的 K48 连接泛素化。与人类 A20 相似,bbtA20 是一种双酶,它可以去除 K63 连接的多泛素链,并在 bbt 受体相互作用丝氨酸/苏氨酸蛋白激酶 1b 上构建 K48 连接的多泛素链,从而抑制 NF-κB 信号通路。我们的研究不仅表明泛素化是调节 NF-κB 激活的一种古老策略,而且还提供了迄今为止在基础脊索动物中 ABINs/A20 通过修饰泛素化蛋白来抑制 NF-κB 的第一个证据,为脊椎动物先天免疫信号的逐步发展提供了信息。