Li Lianyun, Hailey Dale W, Soetandyo Nia, Li Wei, Lippincott-Schwartz Jennifer, Shu Hong-bing, Ye Yihong
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Biochim Biophys Acta. 2008 Jun;1783(6):1140-9. doi: 10.1016/j.bbamcr.2008.01.029. Epub 2008 Feb 19.
A20 is a tumor necrosis factor (TNF)-inducible zinc finger protein that contains both ubiquitinating and deubiquitinating activities. A20 negatively regulates NFkappaB (nuclear factor kappaB) signaling induced by TNF receptor family and Toll-like receptors, but the mechanism of A20 action is poorly defined. Here we show that a fraction of endogenous and ectopically expressed A20 is localized to an endocytic membrane compartment that is in association with the lysosome. The lysosomal association of A20 requires its carboxy terminal zinc finger domains, but is independent of its ubiquitin-modifying activities. Interestingly, A20 mutants defective in membrane association also contain reduced NFkappaB inhibitory activity. These findings suggest the involvement of a lysosome-associated mechanism in A20-dependent termination of NFkappaB signaling.
A20是一种肿瘤坏死因子（TNF）诱导的锌指蛋白，兼具泛素化和去泛素化活性。A20对TNF受体家族和Toll样受体诱导的NFκB（核因子κB）信号传导起负调节作用，但其作用机制尚不明确。在此我们发现，内源性和异位表达的A20的一部分定位于与溶酶体相关的内吞膜区室。A20与溶酶体的结合需要其羧基末端锌指结构域，但与其泛素修饰活性无关。有趣的是，膜结合缺陷的A20突变体的NFκB抑制活性也降低。这些发现表明，溶酶体相关机制参与了A20依赖性的NFκB信号传导终止过程。
