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.

View publisher note:

Averting a Roadblock in Transforming Growth Factor β Signaling

ACKNOWLEDGMENTS

We thank Yan Chen for Smad7^−/− MEFs, Xin-Hua Feng for Smad7 and Smurf1/2 constructs, and Zhe Cai for technical assistance.

This work was supported by grants from the National Natural Science Foundation of China (30930050 and 30921004), the 973 Program of Ministry of Science and Technology of China (2010CB833706 and 2011CB943803), and the Tsinghua University Initiative Scientific Research Program (2010THZ0) to Y.-G.C.