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，当基因突变产生错误折叠的蛋白质时。虽然已经进行了全基因组调查，但在特发性间质性肺炎中尚未发现基因突变。我们重点研究了衰老和氧化应激过程中蛋白质中天冬氨酸的异构化和外消旋化过程，这些过程可以改变三维结构并诱导应激蛋白的产生。在细胞中，蛋白质异构化和外消旋修复酶（PCMT1）的作用是对部分受损的蛋白质进行恢复和再循环。用shRNA载体转染PCMT1基因敲低引起肺泡上皮细胞系A549发生上皮向间质转化。转染后诱导内质网应激标记蛋白GRP78。另一方面，作为肺纤维化的强效诱导剂，TGF β1不能诱导GRP78，而是降低其表达。TGF β1处理后PCMT1的表达量与PCMT1- shrna载体转染后的表达量相当。目前的研究表明，异构体化和外消旋化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.