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

Autor:	Elkouris M; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Kontaki H; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Stavropoulos A; Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece., Antonoglou A; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Nikolaou KC; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Samiotaki M; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Szantai E; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Saviolaki D; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Sideras P; Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece., Panayotou G; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece., Talianidis I; Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece. Electronic address: talianidis@fleming.gr.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2016 Jun 21; Vol. 15 (12), pp. 2733-44. Date of Electronic Publication: 2016 Jun 09.
DOI:	10.1016/j.celrep.2016.05.051
Abstrakt:	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. (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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