Li Lianyun, Soetandyo Nia, Wang Qiuyan, Ye Yihong
Building 5, Room 433, Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 5, center drive, Bethesda, MD 20892, USA.
Biochim Biophys Acta. 2009 Feb;1793(2):346-53. doi: 10.1016/j.bbamcr.2008.09.013. Epub 2008 Oct 8.
The zinc finger-containing protein A20 is a negative regulator of TNF-induced JNK (c-Jun-N-terminal kinase) and NFkappaB (nuclear factor kappaB) 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. 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是肿瘤坏死因子（TNF）诱导的JNK（c-Jun氨基末端激酶）和NFκB（核因子κB）信号通路的负调节因子。A20是一种特殊的酶，兼具泛素化和去泛素化活性。尽管A20主要定位于细胞质中，但我们最近的研究表明，一部分A20能够以一种依赖其羧基末端锌指、但独立于其泛素修饰活性的方式，与溶酶体相互作用区室结合。溶酶体相关的A20在细胞信号传导中是否具有功能尚不清楚。在此，我们证明A20能够将诸如TRAF2等相关信号分子靶向溶酶体进行降解。这一过程依赖于A20的膜锚定锌指结构域，但不需要A20的泛素修饰活性。我们的研究结果提示了一种A20作用的新模式，即涉及将与A20结合的信号分子靶向溶酶体。
