Transforming growth factor beta-1 (TGF beta-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGF beta-1-induced expression of profibrotic proteins, such as fibronectin (FN) and alpha-smooth muscle actin (a-SMA). Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGF beta-1-induced the expression of FN and a-SMA in human lung fibroblast. We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our studies provide a molecular mechanism by which UCHL5 mitigates TGF beta-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target.
[1]Jilin Univ, Hosp 1, Dept Anesthesia, Changchun, Peoples R China.
[2]Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Dept Cell Biol, Pittsburgh, PA 15260 USA.
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