| First Author | Elkouris M | Year | 2016 |
| Journal | Cell Rep | Volume | 15 |
| Issue | 12 | Pages | 2733-44 |
| PubMed ID | 27292644 | Mgi Jnum | J:238299 |
| Mgi Id | MGI:5819011 | Doi | 10.1016/j.celrep.2016.05.051 |
| Citation | Elkouris M, et al. (2016) SET9-Mediated Regulation of TGF-beta Signaling Links Protein Methylation to Pulmonary Fibrosis. Cell Rep 15(12):2733-44 |
| abstractText | TGF-beta 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-beta. We find that the methyltransferase Set9 potentiates TGF-beta 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-beta-dependent expression of genes encoding extracellular matrix components. The inhibitory effect of Set9 on TGF-beta-mediated extracellular matrix production is further demonstrated in mouse models of pulmonary fibrosis. Lung fibrosis induced by bleomycin or Ad-TGF-beta 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. |
