The mRNA-binding protein DDX3 mediates TGF-1 upregulation of translation and promotes pulmonary fibrosis.
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Pulmonary fibrosis is potentiated by a positive feedback loop involving the extracellular sialidase enzyme neuraminidase 3 (NEU3) causing release of active TGF-1 and TGF-1 upregulating NEU3 by increasing translation without affecting mRNA levels. In this report, we elucidate the TGF-1 upregulation of the translation mechanism. In human lung fibroblasts, TGF-1 increased levels of proteins, including NEU3, by increasing translation of the encoding mRNAs without significantly affecting levels of these mRNAs. A total of 180 of these mRNAs shared a common 20-nucleotide motif. Deletion of this motif from NEU3 mRNA eliminated the TGF-1 upregulation of NEU3 translation, while insertion of this motif in 2 mRNAs insensitive to TGF-1 caused TGF-1 to upregulate their translation. RNA-binding proteins including DEAD box helicase 3, X-linked (DDX3), bind the RNA motif, and TGF-1 regulates their protein levels and/or binding to the motif. We found that DDX3 was upregulated in the fibrotic lesions in patients with pulmonary fibrosis, and inhibiting DDX3 in fibroblasts reduced TGF-1 upregulation of NEU3 levels. In the mouse bleomycin model of pulmonary fibrosis, injections of the DDX3 inhibitor RK-33 potentiated survival and reduced lung inflammation, fibrosis, and tissue levels of DDX3, TGF-1, and NEU3. These results suggest that inhibiting an mRNA-binding protein that mediates TGF-1 upregulation of translation can reduce pulmonary fibrosis.
