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

• DOI: 10.1016/j.celrep.2016.05.051
• Publication Date: 2016-06-11T22:55:36Z
• Authors: Maximilianos Elko...; Haroula Kontaki; Athanasios Stavro...; Anastasia Antonoglou; Kostas C. Nikolaou; Martina Samiotaki; Eszter Szantai; Dimitra Saviolaki; Peter J. Brown; Paschalis Sideras; George Panayotou; Iannis Talianidis
• Keywords: Male; 0301 basic medicine; QH301-705.5; Pulmonary Fibrosis; Methylation; Models, Biological; Article; Smad7 Protein; Bleomycin; 03 medical and health sciences; Animals; Humans; Protein Methyltransferases; Biology (General); Mice, Knockout; Protein Stability; Lysine; Nuclear Proteins; Acetylation; Histone-Lysine N-Methyltransferase; Extracellular Matrix; 3. Good health; Mice, Inbred C57BL; Gene Expression Regulation; HeLa Cells; Signal Transduction

TGF-β signaling regulates a variety of cellular processes, including proliferation, apoptosis, differentiation, immune responses, and fibrogenesis. Here, we describe lysine methylation-mediated mechanism that controls the pro-fibrogenic activity TGF-β. We find methyltransferase Set9 potentiates by targeting Smad7, an inhibitory downstream effector. Smad7 methylation promotes interaction with E3 ligase Arkadia and, thus, ubiquitination-dependent degradation. Depletion or pharmacological inhibition results in elevated protein levels inhibits TGF-β-dependent expression genes encoding extracellular matrix components. The effect on TGF-β-mediated production is further demonstrated mouse models pulmonary fibrosis. Lung fibrosis induced bleomycin Ad-TGF-β treatment was highly compromised Set9-deficient mice. These uncover complex regulatory interplay among multiple modifications highlight possibility methyltransferases may represent promising therapeutic targets for treating lung