%0 Journal Article
%T De-ubiquitinating enzyme, USP11, promotes transforming growth factor ¦Â-1 signaling through stabilization of transforming growth factor ¦Â receptor II
%A A M Jacko
%A D J Kass
%A J Tan
%A J Zhao
%A L Nan
%A S Li
%A Y Zhao
%J Archive of "Cell Death & Disease".
%D 2016
%R 10.1038/cddis.2016.371
%X The transforming growth factor ¦Â-1 (TGF¦Â-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGF¦Â-1 receptors, T¦ÂRI and T¦ÂRII, mediate this pathway. T¦ÂRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of T¦ÂRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGF¦Â-1 signaling through de-ubiquitination and stabilization of T¦ÂRII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGF¦Â-1 signaling. Inhibition or downregulation of USP11 results in increases in T¦ÂRII ubiquitination and reduction of T¦ÂRII stability. Subsequently, TGF¦Â-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¦ÂRII ubiquitination and increases T¦ÂRII stabilization, thereby elevating phosphorylation of SMAD2/3 and the ultimate expression of FN and SMA. Further, elevated expression of USP11 and T¦ÂRII 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¦ÂRII and promotion of TGF¦Â-1 signaling. This study provides mechanistic evidence for development of USP11 inhibitors as potential antifibrotic drugs for pulmonary fibrosis
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260874/