Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling
Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagi...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1266198/full |
| _version_ | 1797690084211818496 |
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| author | Ningning Li Lingling Rao Xueqing Zhao Junwen Shen Dan Su Guoqiang Ma Shan Sun Shan Sun Qilian Ma Qilian Ma Li Zhang Chunsheng Dong Kin Yip Tam Jochen H. M. Prehn Hongfeng Wang Zheng Ying |
| author_facet | Ningning Li Lingling Rao Xueqing Zhao Junwen Shen Dan Su Guoqiang Ma Shan Sun Shan Sun Qilian Ma Qilian Ma Li Zhang Chunsheng Dong Kin Yip Tam Jochen H. M. Prehn Hongfeng Wang Zheng Ying |
| author_sort | Ningning Li |
| collection | DOAJ |
| description | Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome–lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy–lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase–mTORC1–TFEB signaling axis in CPZ-induced autophagic impairment. |
| first_indexed | 2024-03-12T01:54:26Z |
| format | Article |
| id | doaj.art-a249e2d9062a453b85a7be08c235801a |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-12T01:54:26Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a249e2d9062a453b85a7be08c235801a2023-09-08T07:24:43ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-09-011110.3389/fcell.2023.12661981266198Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signalingNingning Li0Lingling Rao1Xueqing Zhao2Junwen Shen3Dan Su4Guoqiang Ma5Shan Sun6Shan Sun7Qilian Ma8Qilian Ma9Li Zhang10Chunsheng Dong11Kin Yip Tam12Jochen H. M. Prehn13Hongfeng Wang14Zheng Ying15Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaFaculty of Health Sciences, University of Macau, Taipa, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaDepartment of Physiology and Medical Physics and Future-Neuro Research Centre, Royal College of Surgeons in Ireland, Dublin, IrelandKey Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, ChinaInstitutes of Biology and Medical Science, Soochow University, Suzhou, ChinaFaculty of Health Sciences, University of Macau, Taipa, ChinaDepartment of Physiology and Medical Physics and Future-Neuro Research Centre, Royal College of Surgeons in Ireland, Dublin, IrelandJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, ChinaAutophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome–lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy–lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase–mTORC1–TFEB signaling axis in CPZ-induced autophagic impairment.https://www.frontiersin.org/articles/10.3389/fcell.2023.1266198/fullCPZTFEBautophagymTORC1Rag GTPases |
| spellingShingle | Ningning Li Lingling Rao Xueqing Zhao Junwen Shen Dan Su Guoqiang Ma Shan Sun Shan Sun Qilian Ma Qilian Ma Li Zhang Chunsheng Dong Kin Yip Tam Jochen H. M. Prehn Hongfeng Wang Zheng Ying Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling Frontiers in Cell and Developmental Biology CPZ TFEB autophagy mTORC1 Rag GTPases |
| title | Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling |
| title_full | Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling |
| title_fullStr | Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling |
| title_full_unstemmed | Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling |
| title_short | Chlorpromazine affects autophagy in association with altered Rag GTPase–mTORC1–TFEB signaling |
| title_sort | chlorpromazine affects autophagy in association with altered rag gtpase mtorc1 tfeb signaling |
| topic | CPZ TFEB autophagy mTORC1 Rag GTPases |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1266198/full |
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