title: TSC-22 promotes transforming growth factor β-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity.
abstract: Transforming growth factor β (TGF-β) plays a critical role in tissue fibrosis. The duration and intensity of TGF-β signaling are tightly regulated. Here we report that TSC-22 (TGF-β-stimulated clone 22) facilitates TGF-β signaling by antagonizing Smad7 activity to increase receptor stability. TSC-22 enhances TGF-β-induced Smad2/3 phosphorylation and transcriptional responsiveness. The stimulatory effect of TSC-22 is dependent on Smad7, as silencing Smad7 expression abolishes it. TSC-22 interacts with TGF-β type I receptor TβRI and Smad7 in mutually exclusive ways and disrupts the association of Smad7/Smurfs with TβRI, thereby preventing ubiquitination and degradation of the receptor. We also found that TSC-22 can promote the differentiation of cardiac myofibroblasts by increasing expression of the fibrotic genes for α-smooth muscle actin (α-SMA), PAI-1, fibronectin, and collagen I, which is consistent with upregulation of TSC-22, phospho-Smad2/3, and the fibrotic genes in isoproterenol-induced rat myocardial fibrotic hearts. Taken together with the notion that TGF-β induces TSC-22 expression, our findings suggest that TSC-22 regulates TGF-β signaling via a positive-feedback mechanism and may contribute to myocardial fibrosis.
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yan
authors.forename: Junyu
authors.initials: J
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Xue
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.forename: Xingang
authors.initials: X
authors.lastname: Zhao
authors.forename: Yuanheng
authors.initials: Y
authors.lastname: Ning
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D016212:Transforming Growth Factor beta; C490982:Tsc22d1 protein, rat; C556581:Smurf1 protein, rat; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat