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The transforming growth factor  β -1 (TGF β -1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGF β -1 receptors, T β RI and T β RII, mediate this pathway. T β RI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of T β RII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGF β -1 signaling through de-ubiquitination and stabilization of T β RII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGF β -1 signaling. Inhibition or downregulation of USP11 results in increases in T β RII ubiquitination and reduction of T β RII stability. Subsequently, TGF β -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 β RII ubiquitination and increases T β RII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and T β 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 β RII and promotion of TGF β -1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis.

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