Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Science. 2010 Feb 26;327(5969):1135-9. doi: 10.1126/science.1182364.
A20 negatively regulates inflammation by inhibiting the nuclear factor kappaB (NF-kappaB) transcription factor in the tumor necrosis factor-receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-kappaB signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest mechanism of A20 action in the inhibition of inflammatory signaling pathways.
A20 通过抑制肿瘤坏死因子受体 (TNFR) 和 Toll 样受体 (TLR) 途径中的核因子 kappaB (NF-kappaB) 转录因子来负调控炎症。A20 含有去泛素化酶和 E3 连接酶结构域，因此被提议作为 TNFR1 下游的泛素编辑酶，通过使 RIP1 去泛素化来发挥作用。然而，A20 如何终止 TLR 下游的 NF-kappaB 信号传导仍不清楚。我们已经表明，A20 通过拮抗与 E2 泛素缀合酶 Ubc13 和 UbcH5c 的相互作用，抑制 TRAF6、TRAF2 和 cIAP1 的 E3 连接酶活性。A20 与调节分子 TAX1BP1 相互作用与 Ubc13 和 UbcH5c 并触发它们的泛素化和蛋白酶体依赖性降解。这些发现表明了 A20 在抑制炎症信号通路中的作用机制。
