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

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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.