De-ubiquitinating enzyme, USP11, promotes transforming growth factor β-1 signaling through stabilization of transforming growth factor β receptor II

The transforming growth factor beta-1 (TGF beta-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGF beta-1 receptors, T beta RI and T beta RII, mediate this pathway. T beta RI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of T beta RII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGF beta-1 signaling through de-ubiquitination and stabilization of T beta RII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGF beta-1 signaling. Inhibition or downregulation of USP11 results in increases in T beta RII ubiquitination and reduction of T beta RII stability. Subsequently, TGF beta-1 signaling is greatly attenuated, as shown by the decreases in phosphorylation of SMAD2/3 levels as well as that of fibronectin (FN) and smooth muscle actin (SMA). Overexpression of USP11 reduces T beta RII ubiquitination and increases T beta RII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and T beta RII were detected in lung tissues from bleomycin-challenged mice and IPF patients. Therefore, USP11 may contribute to the pathogenesis of pulmonary fibrosis by stabilization of T beta RII and promotion of TGF beta-1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis.