Jensen Liselotte E, Whitehead Alexander S
Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
FEBS Lett. 2003 Oct 9;553(1-2):190-4. doi: 10.1016/s0014-5793(03)00998-0.
Ubiquitination of intermediates in the interleukin-1 (IL-1) signaling cascade plays an important role in activation and regulation of the pathway. Both IL-1 receptor associated kinase-1 (IRAK1) and inhibitor of nuclear factor kappaB-alpha (IkappaBalpha) are rapidly ubiquitinated and degraded. Tumor necrosis factor associated factor-6 (TRAF6) is an ubiquitin ligase that is activated by ubiquitination and a signaling intermediate between IRAK1 and IkappaBalpha. It is unknown whether activated TRAF6 is subsequently degraded. We show that in liver cells IL-1 stimulates TRAF6 poly-ubiquitination. In less than 1 h levels of non-modified TRAF6 return to levels near those observed prior to activation. TRAF6 cannot be reactivated in cells which have been pretreated with IL-1. This observation correlates with decreased levels of IRAK1 in IL-1 pretreated cells. The re-establishment of non-modified TRAF6 levels following activation does not require de novo protein synthesis, strongly suggesting that TRAF6 is recycled via deubiquitination. This indicates a unique mechanism of regulation of TRAF6 activity.
白细胞介素-1（IL-1）信号级联反应中中间体的泛素化在该信号通路的激活和调节中起着重要作用。白细胞介素-1受体相关激酶-1（IRAK1）和核因子κB抑制因子α（IkappaBalpha）都会迅速被泛素化并降解。肿瘤坏死因子相关因子-6（TRAF6）是一种泛素连接酶，它通过泛素化被激活，是IRAK1和IkappaBalpha之间的信号中间体。目前尚不清楚激活后的TRAF6随后是否会被降解。我们发现，在肝细胞中，IL-1会刺激TRAF6发生多聚泛素化。不到1小时，未修饰的TRAF6水平就会恢复到激活前观察到的水平附近。在已经用IL-1预处理过的细胞中，TRAF6无法被重新激活。这一观察结果与IL-1预处理细胞中IRAK1水平的降低相关。激活后未修饰的TRAF6水平的重新建立不需要从头合成蛋白质，这强烈表明TRAF6是通过去泛素化进行循环利用的。这表明了一种调节TRAF6活性的独特机制。
