The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response
Abstract Background Retinoid-related orphan receptor-α (RORα) and autophagy dysregulation are involved in the pathophysiology of chronic obstructive pulmonary disease (COPD), but little is known regarding their association. We investigated the role of RORα in COPD-related autophagy. Methods The lung...
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BMC
2022-05-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-022-02034-5 |
| _version_ | 1811305833411117056 |
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| author | Hak-Su Kim Chang Hyeok An Danielle Teller Su-Jin Moon Gi Won Hwang Jin Woo Song |
| author_facet | Hak-Su Kim Chang Hyeok An Danielle Teller Su-Jin Moon Gi Won Hwang Jin Woo Song |
| author_sort | Hak-Su Kim |
| collection | DOAJ |
| description | Abstract Background Retinoid-related orphan receptor-α (RORα) and autophagy dysregulation are involved in the pathophysiology of chronic obstructive pulmonary disease (COPD), but little is known regarding their association. We investigated the role of RORα in COPD-related autophagy. Methods The lung tissues and cells from a mouse model were analyzed for autophagy markers by using western blot analysis and transmission electron microscopy. Results Cigarette smoke increased the LC3-II level and decreased the p62 level in whole lung homogenates of a chronic cigarette smoking mouse model. Although cigarette smoke did not affect the levels of p62 in Staggerer mutant mice (RORαsg/sg), the baseline expression levels of p62 were significantly higher than those in wild type (WT) mice. Autophagy was induced by cigarette smoke extract (CSE) in Beas-2B cells and in primary fibroblasts from WT mice. In contrast, fibroblasts from RORαsg/sg mice failed to show CSE-induced autophagy and exhibited fewer autophagosomes, lower LC3-II levels, and higher p62 levels than fibroblasts from WT mice. Damage-regulated autophagy modulator (DRAM), a p53-induced modulator of autophagy, was expressed at significantly lower levels in the fibroblasts from RORαsg/sg mice than in those from WT mice. DRAM knockdown using siRNA in Beas-2B cells inhibited CSE-induced autophagy and cell death. Furthermore, RORα co-immunoprecipitated with p53 and the interaction increased p53 reporter gene activity. Conclusions Our findings suggest that RORα promotes autophagy and contributes to COPD pathogenesis via regulation of the RORα-p53-DRAM pathway. |
| first_indexed | 2024-04-13T08:33:33Z |
| format | Article |
| id | doaj.art-9532e182fe4b4a04b93a75b2d0598588 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-13T08:33:33Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-9532e182fe4b4a04b93a75b2d05985882022-12-22T02:54:11ZengBMCRespiratory Research1465-993X2022-05-0123111010.1186/s12931-022-02034-5The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic responseHak-Su Kim0Chang Hyeok An1Danielle Teller2Su-Jin Moon3Gi Won Hwang4Jin Woo Song5Veterans Health Service Medical Center, Veterans Medical Research InstituteDivision of Pulmonary and Critical Care Medicine, Brigham and Women’s HospitalDivision of Pulmonary and Critical Care Medicine, Brigham and Women’s HospitalDepartment of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of MedicineAbstract Background Retinoid-related orphan receptor-α (RORα) and autophagy dysregulation are involved in the pathophysiology of chronic obstructive pulmonary disease (COPD), but little is known regarding their association. We investigated the role of RORα in COPD-related autophagy. Methods The lung tissues and cells from a mouse model were analyzed for autophagy markers by using western blot analysis and transmission electron microscopy. Results Cigarette smoke increased the LC3-II level and decreased the p62 level in whole lung homogenates of a chronic cigarette smoking mouse model. Although cigarette smoke did not affect the levels of p62 in Staggerer mutant mice (RORαsg/sg), the baseline expression levels of p62 were significantly higher than those in wild type (WT) mice. Autophagy was induced by cigarette smoke extract (CSE) in Beas-2B cells and in primary fibroblasts from WT mice. In contrast, fibroblasts from RORαsg/sg mice failed to show CSE-induced autophagy and exhibited fewer autophagosomes, lower LC3-II levels, and higher p62 levels than fibroblasts from WT mice. Damage-regulated autophagy modulator (DRAM), a p53-induced modulator of autophagy, was expressed at significantly lower levels in the fibroblasts from RORαsg/sg mice than in those from WT mice. DRAM knockdown using siRNA in Beas-2B cells inhibited CSE-induced autophagy and cell death. Furthermore, RORα co-immunoprecipitated with p53 and the interaction increased p53 reporter gene activity. Conclusions Our findings suggest that RORα promotes autophagy and contributes to COPD pathogenesis via regulation of the RORα-p53-DRAM pathway.https://doi.org/10.1186/s12931-022-02034-5Retinoid-related orphan receptor-αChronic obstructive pulmonary diseaseAutophagyp53Damage-regulated autophagy modulator |
| spellingShingle | Hak-Su Kim Chang Hyeok An Danielle Teller Su-Jin Moon Gi Won Hwang Jin Woo Song The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response Respiratory Research Retinoid-related orphan receptor-α Chronic obstructive pulmonary disease Autophagy p53 Damage-regulated autophagy modulator |
| title | The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response |
| title_full | The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response |
| title_fullStr | The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response |
| title_full_unstemmed | The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response |
| title_short | The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response |
| title_sort | role of retinoid related orphan receptor α in cigarette smoke induced autophagic response |
| topic | Retinoid-related orphan receptor-α Chronic obstructive pulmonary disease Autophagy p53 Damage-regulated autophagy modulator |
| url | https://doi.org/10.1186/s12931-022-02034-5 |
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