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.

含锌指的蛋白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，既包含泛素化和去泛素化活性。尽管A20主要位于细胞质中，但我们最近的研究表明，A20的一部分可以与溶酶体相互作用的隔室相连，以需要其羧基终端锌指的手指，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能够靶向相关的信号分子（例如TRAF2）与溶酶体降解。如预期的那样，此过程取决于A20的膜绑定锌指域，但不需要A20泛素修饰活性。我们的发现提出了一种新型的A20作用模式，该模式涉及与A20结合的信号分子的溶酶体靶向。