Liu Fu-You, Li Xiao-Zhao
Department of Nephrology, The Second Xiangya Hospital of Central South University, Middle Ren-Min Road No. 86, Changsha, Hunan 410011, China.
Med Hypotheses. 2006;67(5):1205-7. doi: 10.1016/j.mehy.2006.04.050. Epub 2006 Jun 22.
The ubiquitin-proteasome pathway (UPP) can regulate the stability of proteins, which is regarded as an important mechanism in controlling various biological processes. In the pathway, E3 ubiquitin ligases play critical roles in the recognition of target proteins and degradation by 26S proteasomes. Arkadia is one of the E3 ubiquitin ligases, and recent research has shown that Arkadia amplifies TGF-beta signalling through degradation of Smad7. The cellular level of Smad7 plays an important role in the regulation of Smad-mediated TGF-beta signalling during progression of organ fibrosis. Studies indicate that the level of Smad7 protein expression is decreased in progression of tubulointerstitial fibrosis. Moreover, growing evidence suggests renal tubular epithelial to mesenchymal transition (EMT) plays a key role in renal tubulointerstitial fibrosis and transforming growth factor-beta(1) (TGF-beta(1)) is the most potent inducer that is capable of initiating and completing the entire EMT course. Therefore, the activation of Smad signalling induced by TGF-beta(1) plays a key role in the mechanism of renal tubular EMT, and in this process, Arkadia may has an important influence on the mechanism above mentioned through degradation of Smad7.
泛素-蛋白酶体途径（UPP）可调节蛋白质的稳定性，这被视为控制各种生物过程的重要机制。在该途径中，E3泛素连接酶在识别靶蛋白以及被26S蛋白酶体降解的过程中发挥关键作用。Arkadia是E3泛素连接酶之一，最近的研究表明，Arkadia通过降解Smad7来放大TGF-β信号传导。在器官纤维化进展过程中，Smad7的细胞水平在调节Smad介导的TGF-β信号传导中起重要作用。研究表明，在肾小管间质纤维化进展过程中，Smad7蛋白表达水平降低。此外，越来越多的证据表明，肾小管上皮向间充质转化（EMT）在肾小管间质纤维化中起关键作用，而转化生长因子-β1（TGF-β1）是能够启动并完成整个EMT过程的最有效诱导剂。因此，TGF-β1诱导的Smad信号激活在肾小管EMT机制中起关键作用，在此过程中，Arkadia可能通过降解Smad7对上述机制产生重要影响。
