The role of amino acid isomerization and racemization in the pathogenesis of interstitial pnuemonia

热休克蛋白参与特发性间质性肺炎的发病机制，当由于基因突变而产生错误折叠的蛋白时。虽然已经进行了全基因组研究，但尚未在特发性间质性肺炎中发现基因突变。我们重点研究了蛋白质中天冬氨酸在衰老和氧化应激过程中的异构化和外消旋，这些异构化和消旋化可以改变蛋白质的三维结构，诱导应激蛋白质的产生。在细胞中，存在蛋白质异构化和消旋化修复酶(PCMT1)，用于部分受损蛋白质的恢复和循环。将PCMT1基因导入shRNA载体，使肺泡上皮细胞系A549发生上皮细胞向间充质细胞的转化。表达产物为内质网应激标记蛋白GRP78。另一方面，转化生长因子β-1是肺纤维化的有效诱导剂，但不能诱导GRP78的表达，而是减少表达。经转化生长因子β-1处理后，PCMT1的表达水平与PCMT1-shRNA载体转染组相当。目前的研究表明，异构化和消旋化的错误折叠蛋白积累的新的分子机制可能是特发性间质性肺炎的原因之一。

Heat shock proteins are involved in the pathogenesis of idiopathic interstitial pneumonia, when misfolded proteins as a consequence of genetic mutations are generated. Although genome wide investigations have been performed, genetic mutations have not been identified in idiopathic interstitial pneumonia. We focused on isomerization and racemization of aspartic acid in the proteins during aging and oxidative stress, which can change three dimensional structure and induce stress proteins productions. In the cells, protein isomerization and racemization repair enzyme (PCMT1) exists for recovery and recycle of the partially damaged proteins. An alveolar epithelial cell line, A549, was subjected to epithelial-to-mesenchymal transition that was caused by PCMT1 gene knock down transfected with shRNA vector. The endoplasmic reticulum stress marker protein, GRP78, was induced after transfection. On the other hand, TGF β1, which is a potent inducer of fibrosis in the lung, could not induce GRP78, rather decreased expression. The expression of PCMT1 with TGF β1 treatment was comparable with the value found by PCMT1-shRNA vector transfection. The current study indicated that the novel molecular mechanism by accumulation of isomerized and racemized misfolded proteins seems to be one of causes of idiopathic interstitial pneumonia.