SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis.
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.
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Maximilianos
M
Elkouris
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Haroula
H
Kontaki
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Athanasios
A
Stavropoulos
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Anastasia
A
Antonoglou
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Kostas C
KC
Nikolaou
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Martina
M
Samiotaki
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Eszter
E
Szantai
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
Dimitra
D
Saviolaki
Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
Peter J
PJ
Brown
Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Paschalis
P
Sideras
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece.
George
G
Panayotou
Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece. Electronic address: talianidis@fleming.gr.
Iannis
I
Talianidis
D000107:Acetylation; D000818:Animals; D001761:Bleomycin; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D011496:Protein Methyltransferases / Q000378:metabolism*; D055550:Protein Stability; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
D009687:Nuclear Proteins; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C562044:Setd7 protein, mouse; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine