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: 7734089
• 负责人: Yihong Ye
• 金额: $ 25.14万
• 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/7734089
• 关键词: A20 protein; Address; Binding; Complement Factor B; Cytosol; Enzymes; Localized; Lysosomes; Membrane; Nuclear; Process; Proteins; Regulation; Signal Transduction; Signaling Molecule; TNF receptor-associated factor 2; TRAF2 gene; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ubiquitin; Zinc Fingers; human TNF protein; 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）信号传导的负调节剂。A20是一种不寻常的酶，同时具有泛素化和去泛素化活性。虽然A20主要定位于胞质溶胶中，但我们最近的研究表明，A20的一部分可以以需要其羧基末端锌指的方式与溶酶体相互作用隔室相关联，但独立于其泛素修饰活性。溶酶体相关的A20是否在细胞信号传导中起作用尚不清楚。 在这里，我们证明了A20能够将相关的信号分子如TRAF 2靶向溶酶体进行降解。正如预期的，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，一种新的模式A20的行动，涉及溶酶体靶向信号分子结合到A20。