Regulation of RNA Binding Proteins in the Pathogenesis of Lung Fibrosis

RNA binding proteins (RBPs) associate with target RNAs through conventional or unconventional RNA-binding domains to regulate all aspects of mRNA biogenesis and metabolism. Under certain settings like cellular stress, membrane-less cytoplasmic aggregates termed stress granules (SGs) are formed which enclose RBPs and untranslated or stalled RNA transcripts. In organs with a high and complex RNA metabolism like the brain or the lungs, the tasks of RBPs and SGs become even more important. The complex role of RBPs has been elegantly studied in neurodegeneration but their role remains poorly understood in several lung diseases. Idiopathic pulmonary fibrosis (IPF) is a life-threatening chronic lung disease that is characterized by alveolar epithelial cell injury and severe fibroblast proliferation thereby resulting in disturbed epithelial-mesenchymal crosstalk and ultimately fibrosis. The goal of this study is to understand the role of RBPs and SGs in lung fibrosis. For this, explanted lungs and interstitial fibroblasts isolated from IPF patients or healthy donors as well as mouse model and in vitro of amiodarone induced lung fibrosis were exploited. In general, differential regulation of seve ral RBPs including TDP43, FUS, SRF, MBNL1 and PABPC1 were observed in IPF and in the amiodarone model. Of interest, the stress granule associated protein, PABPC1 was observed to be particularly increased in the interstitial fibroblasts of IPF patients. Immunohistochemistry revealed that most of the studied RBPs were stained extensively in the nucleus as well as in the cytoplasm of the alveolar epithelial cells of IPF patients while RBPs were majorly stained within the nucleus in donor lungs. Taken together, our first line of results show altered localization of RBPs and SG proteins in IPF patient lungs, suggesting their altered regulation in this disease which may contribute towards the pathophysiology of IPF.