Regulation of TNFa signaling by the dual ubiquitin modifying enzyme 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是一种罕见的酶，具有泛素化和去泛素化活性。虽然A20主要定位于细胞质中，但我们最近的研究表明，A20的一部分可以以一种需要其羧基末端锌指的方式与溶酶体相互作用室结合，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能够靶向相关的信号分子，如TRAF2到溶酶体降解。正如预期的那样，这一过程依赖于A20的锌指结构域的膜系结，但不需要A20泛素修饰活性。我们的发现提示了一种新的A20作用模式，包括溶酶体靶向与A20结合的信号分子。

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.