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

Summary

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.

Graphical Abstract

Highlights

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  Set9 (Setd7) methylates Smad7 at lysine-70

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  Methylated Smad7 interacts with Arkadia and is rapidly degraded

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  Set9 function is required for TGF-β-mediated activation of ECM genes

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  Set9 function is required for bleomycin- or Ad-TGF-β-induced pulmonary fibrosis

Abstract

Elkouris et al. find that Set9 regulates the TGF-β-signaling pathway and is required for the development of pulmonary fibrosis in mice. The authors find that Set9-mediated methylation of inhibitory Smad7 leads to its degradation, thus affecting TGF-β-dependent activation of extracellular matrix genes.