Regulation of TNFa signaling by the dual ubiquitin modifying enzyme A20

双泛素修饰酶 A20 对 TNFa 信号传导的调节

• 批准号: 7967367
• 负责人: Yihong Ye
• 金额: $ 19.72万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967367
• 关键词: A20 protein; Address; Binding; Complement Factor B; Cytosol; Enzymes; Lysosomes; Membrane; Nuclear; Process; Proteins; Regulation; Signal Transduction; Signaling Molecule; TRAF2 gene; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ubiquitin; Zinc Fingers; novel; stress-activated protein kinase 1

The zinc finger-containing protein A20 is a negative regulator of TNF-induced JNK (c-Jun-N-terminal kinase) and NFB (nuclear factor B) signaling. A20 is an unusual enzyme that contains both ubiquitinating and deubiquitinating activities. Although A20 is mostly localized in the cytosol, our recent studies reveal that a fraction of A20 can associate with a lysosome-interacting compartment in a manner that requires its carboxy terminal zinc fingers, but independent of its ubiquitin modifying activities. Whether the lysosome-associated A20 has a function in cellular signaling is unclear. Here, we demonstrate that A20 is capable of targeting an associated signaling molecule such as TRAF2 to the lysosomes for degradation. As expected, this process is dependent on the membrane tethering zinc finger domains of A20, but does not require A20 ubiquitin modifying activity. Our findings suggest a novel mode of A20 action that involves lysosomal targeting of signal molecules bound to A20.

含锌指蛋白 A20 是 TNF 诱导的 JNK（c-Jun-N 末端激酶）和 NFB（核因子 B）信号传导的负调节因子。 A20 是一种不寻常的酶，具有泛素化和去泛素化活性。尽管 A20 大部分位于细胞质中，但我们最近的研究表明，一小部分 A20 可以以需要其羧基末端锌指的方式与溶酶体相互作用的区室结合，但与其泛素修饰活性无关。溶酶体相关的 A20 是否在细胞信号传导中具有功能尚不清楚。 在这里，我们证明 A20 能够将相关信号分子（例如 TRAF2）靶向溶酶体进行降解。正如预期的那样，该过程依赖于 A20 的膜束缚锌指结构域，但不需要 A20 泛素修饰活性。我们的研究结果表明 A20 作用的一种新模式涉及与 A20 结合的信号分子的溶酶体靶向。