SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis
In contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-...
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MDPI AG
2020-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/7/996 |
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| author | Raanan Bulvik Raphael Breuer Mona Dvir-Ginzberg Eli Reich Neville Berkman Shulamit B. Wallach-Dayan |
| author_facet | Raanan Bulvik Raphael Breuer Mona Dvir-Ginzberg Eli Reich Neville Berkman Shulamit B. Wallach-Dayan |
| author_sort | Raanan Bulvik |
| collection | DOAJ |
| description | In contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (<i>H355Y</i>-<i>Sirt1<sup>y/y</sup></i>), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis. |
| first_indexed | 2024-03-10T18:42:22Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T18:42:22Z |
| publishDate | 2020-07-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-42c7740c9f064ccfaa78579288e5c3822023-11-20T05:42:21ZengMDPI AGBiomolecules2218-273X2020-07-0110799610.3390/biom10070996SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-FibrosisRaanan Bulvik0Raphael Breuer1Mona Dvir-Ginzberg2Eli Reich3Neville Berkman4Shulamit B. Wallach-Dayan5Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah—Hebrew University Medical Center, POB 12000, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah—Hebrew University Medical Center, POB 12000, Jerusalem 91120, IsraelInstitute of Dental Sciences, Faculty of Dental Medicine, Hebrew University-Hadassah, POB 12065, Jerusalem 9112102, IsraelInstitute of Dental Sciences, Faculty of Dental Medicine, Hebrew University-Hadassah, POB 12065, Jerusalem 9112102, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah—Hebrew University Medical Center, POB 12000, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah—Hebrew University Medical Center, POB 12000, Jerusalem 91120, IsraelIn contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (<i>H355Y</i>-<i>Sirt1<sup>y/y</sup></i>), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis.https://www.mdpi.com/2218-273X/10/7/996myofibroblastsSIRT1cell-deathFLIPKu70IPF-resolution |
| spellingShingle | Raanan Bulvik Raphael Breuer Mona Dvir-Ginzberg Eli Reich Neville Berkman Shulamit B. Wallach-Dayan SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis Biomolecules myofibroblasts SIRT1 cell-death FLIP Ku70 IPF-resolution |
| title | SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis |
| title_full | SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis |
| title_fullStr | SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis |
| title_full_unstemmed | SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis |
| title_short | SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis |
| title_sort | sirt1 deficiency specifically in fibroblasts decreases apoptosis resistance and is associated with resolution of lung fibrosis |
| topic | myofibroblasts SIRT1 cell-death FLIP Ku70 IPF-resolution |
| url | https://www.mdpi.com/2218-273X/10/7/996 |
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