Blocking core fucosylation of TGF-β1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells
Blocking core fucosylation of TGF-β1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells
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DOI：
10.1152/ajprenal.00426.2010
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Shan, Lujuan
中科院分区：
文献类型：
--
作者：
Lin, Hongli;Wang, Dapeng;Shan, Lujuan
林华，王东，吴涛，董超，沈南，孙勇，孙勇，谢华，王宁，单力。阻断转化生长因子-β1受体的核心岩藻糖基化可下调其功能，抑制肾小管上皮细胞向间充质细胞的转化。Am J Physiol Renal Physiol 300：F1017-F1025,2011。首次发表于2011年1月12日；对蛋白质的doi:10.1152/ajprenal.00426.2010.-Posttranslational修饰可以调节它们的多种生物学功能。转化生长因子-β受体I和II(Alk5和TGF-βRII)是一种糖蛋白，在肾小管上皮-间充质转化过程中发挥重要作用。在本研究中，我们研究了由α-1，6岩藻糖基转移酶(Fut8)调控的转化生长因子-βRII和碱性磷酸酶(Alk5)的核心岩藻糖基化在培养的人肾近端小管上皮细胞(HK-2)EMT过程中的作用。为研究核心岩藻糖基化在EMT中的作用，构建了转化生长因子-β1诱导的EMT的典型细胞模型。核心岩藻糖基化是转化生长因子-βRII和碱性磷酸酶5完成其功能所必需的，用Fut8小干扰RNA阻断核心岩藻糖基化可显著降低Smad2/3蛋白的磷酸化，导致转化生长因子-β/Smad2/3信号失活，从而导致EMT的缓解。更重要的是，即使在高水平表达转化生长因子-β1、转化生长因子-βRII和碱性蛋白5的情况下，阻断核心岩藻糖基化也可以减弱HK-2细胞的EMT。因此，阻断转化生长因子-βRII和Alk5的核心岩藻糖基化可能独立于这些蛋白的表达而减弱EMT。这项研究可能为糖基化在肾间质纤维化中的作用提供新的见解。此外，核心岩藻糖基化可能是治疗肾小管上皮细胞癌的新的潜在治疗靶点。
Lin H, Wang D, Wu T, Dong C, Shen N, Sun Y, Sun Y, Xie H, Wang N, Shan L. Blocking core fucosylation of TGF-beta 1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells. Am J Physiol Renal Physiol 300: F1017-F1025, 2011. First published January 12, 2011; doi:10.1152/ajprenal.00426.2010.-Posttranslational modification of proteins could regulate their multiple biological functions. Transforming growth factor-beta receptor I and II (ALK5 and TGF-beta RII), which are glycoproteins, play important roles in the renal tubular epithelial-mesenchymal transition (EMT). In the present study, we examined the role of core fucosylation of TGF-beta RII and ALK5, which is regulated by alpha-1,6 fucosyltransferase (Fut8), in the process of EMT of cultured human renal proximal tubular epithelial (HK-2) cells. The typical cell model of EMT induced by TGF-beta 1 was constructed to address the role of core fucosylation in EMT. Core fucosylation was found to be essential for both TGF-beta RII and ALK5 to fulfill their functions, and blocking it with Fut8 small interfering RNA greatly reduced the phosphorylation of Smad2/3 protein, caused the inactivation of TGF-beta/Smad2/3 signaling, and resulted in remission of EMT. More importantly, even with high levels of expressions of TGF-beta 1, TGF-beta RII, and ALK5, blocking core fucosylation also could attenuate the EMT of HK-2 cells. Thus blocking core fucosylation of TGF-beta RII and ALK5 may attenuate EMT independently of the expression of these proteins. This study may provide new insight into the role of glycosylation in renal interstitial fibrosis. Furthermore, core fucosylation may be a novel potential therapeutic target for treatment of renal tubular EMT.