Transforming growth factor β1 alters the 3'-UTR of mRNA to promote lung fibrosis.

Autor:	Ko J; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030.; MD Anderson UTHealth Graduate School, the University of Texas Health Science Center, Houston, Texas 77030., Mills T; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030., Huang J; Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003 Jiangsu, China., Chen NY; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030., Mertens TCJ; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030., Collum SD; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030.; MD Anderson UTHealth Graduate School, the University of Texas Health Science Center, Houston, Texas 77030., Lee G; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030., Xiang Y; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030., Han L; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030.; MD Anderson UTHealth Graduate School, the University of Texas Health Science Center, Houston, Texas 77030., Zhou Y; Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912., Lee CG; Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912., Elias JA; Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912., Jyothula SSK; Department of Internal Medicine, McGovern Medical School, the University of Texas Health Science Center, Houston, Texas 77030., Rajagopal K; Department of Internal Medicine, McGovern Medical School, the University of Texas Health Science Center, Houston, Texas 77030., Karmouty-Quintana H; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030.; MD Anderson UTHealth Graduate School, the University of Texas Health Science Center, Houston, Texas 77030., Blackburn MR; Department of Biochemistry and Molecular Biology, the University of Texas Health Science Center, Houston, Texas 77030 Michael.R.Blackburn@uth.tmc.edu.; MD Anderson UTHealth Graduate School, the University of Texas Health Science Center, Houston, Texas 77030.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Oct 25; Vol. 294 (43), pp. 15781-15794. Date of Electronic Publication: 2019 Sep 05.
DOI:	10.1074/jbc.RA119.009148
Abstrakt:	Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by the pathological remodeling of air sacs as a result of excessive accumulation of extracellular matrix (ECM) proteins, but the mechanism governing the robust protein expression is poorly understood. Our recent findings demonstrate that alternative polyadenylation (APA) caused by NUDT21 reduction is important for the increased expression of fibrotic mediators and ECM proteins in lung fibroblasts by shortening the 3'-untranslated regions (3'-UTRs) of mRNAs and stabilizing their transcripts, therefore activating pathological signaling pathways. Despite the importance of NUDT21 reduction in the regulation of fibrosis, the underlying mechanisms for the depletion are unknown. We demonstrate here that NUDT21 is depleted by TGFβ1. We found that miR203, which is increased in IPF, was induced by TGFβ1 to target the NUDT21 3'-UTR, thus depleting NUDT21 in human and mouse lung fibroblasts. TGFβ1-mediated NUDT21 reduction was attenuated by the miR203 inhibitor antagomiR203 in fibroblasts. TGFβ1 transgenic mice revealed that TGFβ1 down-regulates NUDT21 in fibroblasts in vivo Furthermore, TGFβ1 promoted differential APA of fibrotic genes, including FGF14, RICTOR, TMOD2, and UCP5, in association with increased protein expression. This unique differential APA signature was also observed in IPF fibroblasts. Altogether, our results identified TGFβ1 as an APA regulator through NUDT21 depletion amplifying pulmonary fibrosis. (© 2019 Ko et al.)
Databáze:	MEDLINE
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