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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.

Author information

1
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
2
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
3
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
4
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece. Electronic address: talianidis@fleming.gr.

Abstract

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.

PMID:
27292644
PMCID:
PMC4920893
DOI:
10.1016/j.celrep.2016.05.051
[Indexed for MEDLINE]
Free PMC Article

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