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Cell Rep. 2016 Jun 21;15(12):2733-44. doi: 10.1016/j.celrep.2016.05.051. Epub 2016 Jun 9.

SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis.

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Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece. Electronic address:


TGF-β signaling regulates a variety of cellular processes, including proliferation, apoptosis, differentiation, immune responses, and fibrogenesis. Here, we describe a lysine methylation-mediated mechanism that controls the pro-fibrogenic activity of TGF-β. We find that the methyltransferase Set9 potentiates TGF-β signaling by targeting Smad7, an inhibitory downstream effector. Smad7 methylation promotes interaction with the E3 ligase Arkadia and, thus, ubiquitination-dependent degradation. Depletion or pharmacological inhibition of Set9 results in elevated Smad7 protein levels and inhibits TGF-β-dependent expression of genes encoding extracellular matrix components. The inhibitory effect of Set9 on TGF-β-mediated extracellular matrix production is further demonstrated in mouse models of pulmonary fibrosis. Lung fibrosis induced by bleomycin or Ad-TGF-β treatment was highly compromised in Set9-deficient mice. These results uncover a complex regulatory interplay among multiple Smad7 modifications and highlight the possibility that protein methyltransferases may represent promising therapeutic targets for treating lung fibrosis.

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