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 po...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716306490 |
| _version_ | 1818179126566060032 |
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| author | Maximilianos Elkouris Haroula Kontaki Athanasios Stavropoulos Anastasia Antonoglou Kostas C. Nikolaou Martina Samiotaki Eszter Szantai Dimitra Saviolaki Peter J. Brown Paschalis Sideras George Panayotou Iannis Talianidis |
| author_facet | Maximilianos Elkouris Haroula Kontaki Athanasios Stavropoulos Anastasia Antonoglou Kostas C. Nikolaou Martina Samiotaki Eszter Szantai Dimitra Saviolaki Peter J. Brown Paschalis Sideras George Panayotou Iannis Talianidis |
| author_sort | Maximilianos Elkouris |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T20:58:55Z |
| format | Article |
| id | doaj.art-d6d19049a7334b35a8b9cfd507b446c8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T20:58:55Z |
| publishDate | 2016-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d6d19049a7334b35a8b9cfd507b446c82022-12-22T00:51:02ZengElsevierCell Reports2211-12472016-06-0115122733274410.1016/j.celrep.2016.05.051SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary FibrosisMaximilianos Elkouris0Haroula Kontaki1Athanasios Stavropoulos2Anastasia Antonoglou3Kostas C. Nikolaou4Martina Samiotaki5Eszter Szantai6Dimitra Saviolaki7Peter J. Brown8Paschalis Sideras9George Panayotou10Iannis Talianidis11Biomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Research Foundation, Academy of Athens, Athens 11527, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceStructural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, CanadaBiomedical Research Foundation, Academy of Athens, Athens 11527, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceBiomedical Sciences Research Center Alexander Fleming, Vari 16672, GreeceTGF-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.http://www.sciencedirect.com/science/article/pii/S2211124716306490 |
| spellingShingle | Maximilianos Elkouris Haroula Kontaki Athanasios Stavropoulos Anastasia Antonoglou Kostas C. Nikolaou Martina Samiotaki Eszter Szantai Dimitra Saviolaki Peter J. Brown Paschalis Sideras George Panayotou Iannis Talianidis SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis Cell Reports |
| title | SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis |
| title_full | SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis |
| title_fullStr | SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis |
| title_full_unstemmed | SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis |
| title_short | SET9-Mediated Regulation of TGF-β Signaling Links Protein Methylation to Pulmonary Fibrosis |
| title_sort | set9 mediated regulation of tgf β signaling links protein methylation to pulmonary fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716306490 |
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