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- W4307528104 abstract "Abstract In human lung cells, the profibrotic cytokine TGF-β1 increases sialidase 3 (NEU3) protein by increasing NEU3 translation without increasing levels of NEU3 mRNA. To elucidate how TGF-β1 regulates translation, we treated human lung fibroblasts (HLF) with TGF-β1 and used proteomics and RNA-seq to determine the effect of TGF-β1 on proteins, mRNAs, and mRNA polysome/monosome ratios. We identified 181 mRNAs where TGF-β1 also increases translation to increase protein levels without significantly affecting mRNA levels. These mRNAs share a common 20 nucleotide motif. Deletion or insertion of this motif in mRNAs eliminates or induces the TGF-β1 regulation of translation. At least 5 RNA-binding proteins including DDX3 bind the RNA motif, and TGF-β1 regulates their protein levels and/or binding to the motif. Inhibiting DDX3, either by siRNA or small molecule inhibitors, reduced TGF-β1 induced NEU3 levels. In the mouse bleomycin model of pulmonary fibrosis, injections of the DDX3 inhibitor RK-33 starting 10 days after bleomycin potentiated survival and reduced lung inflammation, fibrosis, and lung tissue levels of DDX3, TGF-β1, and NEU3. Together, these results suggest that TGF-β1 regulates RNA-binding proteins that interact with a mRNA motif that is necessary and sufficient for TGF-β1 to regulate mRNA translation, and that blocking this effect can reduce fibrosis." @default.
- W4307528104 created "2022-11-02" @default.
- W4307528104 creator A5028452183 @default.
- W4307528104 creator A5089426600 @default.
- W4307528104 date "2022-10-23" @default.
- W4307528104 modified "2023-10-17" @default.
- W4307528104 title "Inhibiting a mRNA motif binding protein that mediates TGF-β1 upregulation of translation attenuates pulmonary fibrosis in mice" @default.
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- W4307528104 doi "https://doi.org/10.1101/2022.10.23.513405" @default.
- W4307528104 hasPublicationYear "2022" @default.
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