Journal
CELL REPORTS
Volume 15, Issue 12, Pages 2733-2744Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.051
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Funding
- European Union (European Research Council [ERC] Advanced Investigator Grant) [ERC-2011-AdG294464]
- FP7 Marie Curie ITN [PITN-GA-2013-606806]
- European Regional Development Fund (ERDF)-GSRT grant [ARISTEIA II-3451]
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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.
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