αB-crystallin is essential for the TGF-β2-mediated epithelial to mesenchymal transition of lens epithelial cells.
αB-crystallin is essential for the TGF-β2-mediated epithelial to mesenchymal transition of lens epithelial cells.
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DOI：
10.1042/bcj20160128
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发表时间：
2016-05-15
期刊：
影响因子：
--
通讯作者：
Nagaraj RH
中科院分区：
文献类型：
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作者：
Nahomi RB;Pantcheva MB;Nagaraj RH
转化生长因子（Transforming growth factor，TGF）-β2介导的途径在继发性白内障形成过程中透镜上皮细胞（epithelial to mesenchymal transition，EMT）的发生中起重要作用，也称为后囊膜混浊（posterior capsule opacification，PCO）。虽然α B-晶状体蛋白是LEC中的主要蛋白质，但其在EMT中的作用尚不清楚。在人LEC系（FHL 124）中，TGF-β2处理导致EMT相关蛋白在mRNA和蛋白水平上的变化。这与α B-晶状体蛋白、磷酸化Smad 2（S245/250/255）、Smad 3（S423/425）、Smad 4和Snail的核定位以及α B-晶状体蛋白与这些转录因子的结合有关，所有这些都因α B-晶状体蛋白的下调而减少。α B-晶状体蛋白功能缺陷R120 G突变体的表达减少了α B-晶状体蛋白敲除（KO）小鼠LEC中TGF-β2诱导的EMT。用TGF-β2处理牛透镜上皮组织和小鼠LEC，导致EMT相关蛋白在mRNA和蛋白水平上发生变化。与未处理的细胞相比，这伴随着p44/42丝裂原活化蛋白激酶（MAPK）（T202/Y204）、p38 MAPK（T180/Y182）、蛋白激酶B（Akt）（S473）和Smad 2的磷酸化增加。这些变化在α B-晶状体蛋白耗尽或敲除的LEC中显著减少。从野生型（WT）小鼠的透镜中去除纤维细胞团导致囊膜粘附上皮细胞中EMT相关基因上调，而α B-晶状体蛋白KO小鼠中EMT相关基因下调。总之，我们的数据表明，α B-晶状体蛋白在TGF-β2诱导的LEC EMT中起着核心作用。α B-晶状体蛋白可作为靶点预防PCO和其他组织病理性纤维化。
Transforming growth factor (TGF)-β2-mediated pathways play a major role in the epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) during secondary cataract formation, which is also known as posterior capsule opacification (PCO). Although αB-crystallin is a major protein in LEC, its role in the EMT remains unknown. In a human LEC line (FHL124), TGF-β2 treatment resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was associated with nuclear localization of αB-crystallin, phosphorylated Smad2 (pSmad2) (S245/250/255), pSmad3 (S423/425), Smad4 and Snail and the binding of αB-crystallin to these transcription factors, all of which were reduced by the down-regulation of αB-crystallin. Expression of the functionally defective R120G mutant of αB-crystallin reduced TGF-β2-induced EMT in LECs of αB-crystallin knockout (KO) mice. Treatment of bovine lens epithelial explants and mouse LEC with TGF-β2 resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was accompanied by increase in phosphorylation of p44/42 mitogen-activated protein kinases (MAPK) (T202/Y204), p38 MAPK (T180/Y182), protein kinase B (Akt) (S473) and Smad2 when compared with untreated cells. These changes were significantly reduced in αB-crystallin depleted or knocked out LEC. The removal of the fibre cell mass from the lens of wild-type (WT) mice resulted in the up-regulation of EMT-associated genes in the capsule-adherent epithelial cells, which was reduced in the αB-crystallin KO mice. Together, our data show that αB-crystallin plays a central role in the TGF-β2-induced EMT of LEC. αB-Crystallin could be targeted to prevent PCO and pathological fibrosis in other tissues.