Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0451, USA.
Immunity. 2013 May 23;38(5):896-905. doi: 10.1016/j.immuni.2013.03.008. Epub 2013 Apr 18.
A20 is an anti-inflammatory protein linked to multiple human autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20(OTU) proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling.
A20 是一种与多种人类自身免疫性疾病和淋巴瘤相关的抗炎蛋白。A20 具有去泛素化基序和锌指 ZF4，ZF4 可结合泛素并支持其 E3 泛素连接酶活性。为了了解这些活性如何介导 A20 的生理功能，我们生成了两条基因靶向小鼠品系，分别消除 A20 的去泛素化活性（Tnfaip3(OTU) 小鼠）或 A20 的 ZF4（Tnfaip3(ZF4) 小鼠）。两种 Tnfaip3(OTU) 和 Tnfaip3(ZF4) 小鼠对 TNF 的反应增强，对结肠炎的敏感性增加。A20 的 C103 去泛素化基序限制了受体相互作用蛋白 1（RIP1）的 K48 和 K63 连接的泛素化。A20 的 ZF4 对于招募结合泛素化 RIP1 的 A20 是必需的。A20(OTU) 蛋白和 A20(ZF4) 蛋白相互补充，以正常调节 RIP1 泛素化和 NFκB 信号在复合突变 Tnfaip3(OTU/ZF4) 细胞中。这种互补作用涉及 A20 蛋白的同源二聚化，我们已经在 A20 中定义了一个广泛的二聚化界面。这些研究揭示了 A20 蛋白如何协作以限制 TNF 信号。
