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

被引：68

作者：

Elkouris, Maximilianos ^{[1
]}

Kontaki, Haroula ^{[1
]}

Stavropoulos, Athanasios ^{[2
]}

Antonoglou, Anastasia ^{[1
]}

Nikolaou, Kostas C. ^{[1
]}

Samiotaki, Martina ^{[1
]}

Szantai, Eszter ^{[1
]}

Saviolaki, Dimitra ^{[1
]}

Brown, Peter J. ^{[3
]}

Sideras, Paschalis ^{[2
]}

Panayotou, George ^{[1
]}

Talianidis, Iannis ^{[1
]}

机构：

[1] Biomed Sci Res Ctr Alexander Fleming, Vari 16672, Greece

[2] Acad Athens, Biomed Res Fdn, Athens 11527, Greece

[3] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

来源：

CELL REPORTS | 2016年 / 15卷 / 12期

基金：

欧洲研究理事会;

关键词：

GROWTH-FACTOR-BETA; LYSINE METHYLATION; MESENCHYMAL TRANSITION; UBIQUITIN LIGASE; SMAD7; STABILITY; LUNG FIBROSIS; DEGRADATION; MECHANISMS; CANCER; RECEPTOR;

D O I：

10.1016/j.celrep.2016.05.051

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2733 / 2744

页数：12

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