{"doi":"10.1101/2022.10.23.513405","title":"Inhibiting a mRNA motif binding protein that mediates TGF-β1 upregulation of translation attenuates pulmonary fibrosis in mice","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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304690,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.964,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":334970,"name":"Darrell Pilling","orcid":"0000-0002-7413-2773","position":1,"is_corresponding":false},{"id":347906,"name":"Richard H. Gomer","orcid":"0000-0003-2361-4307","position":2,"is_corresponding":false},{"id":911015,"name":"Wensheng Chen","orcid":"0000-0002-2853-8422","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:37.185846Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}