The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila
Abstract cAMP Responsible Element Binding Protein (CREB) is an evolutionarily conserved transcriptional factor that regulates cell growth, synaptic plasticity and so on. In this study, we unexpectedly found proteasome inhibitors, such as MLN2238, robustly increase CREB activity in adult flies throug...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05122-y |
| _version_ | 1811315162859175936 |
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| author | Youjie Yin Peng Ma Saifei Wang Yao Zhang Ruolei Han Chunyu Huo Meixian Wu Hansong Deng |
| author_facet | Youjie Yin Peng Ma Saifei Wang Yao Zhang Ruolei Han Chunyu Huo Meixian Wu Hansong Deng |
| author_sort | Youjie Yin |
| collection | DOAJ |
| description | Abstract cAMP Responsible Element Binding Protein (CREB) is an evolutionarily conserved transcriptional factor that regulates cell growth, synaptic plasticity and so on. In this study, we unexpectedly found proteasome inhibitors, such as MLN2238, robustly increase CREB activity in adult flies through a large-scale compound screening. Mechanistically, reactive oxidative species (ROS) generated by proteasome inhibition are required and sufficient to promote CREB activity through c-Jun N-terminal kinase (JNK). In 293 T cells, JNK activation by MLN2238 is also required for increase of CREB phosphorylation at Ser133. Meanwhile, transcriptome analysis in fly intestine identified a group of genes involved in redox and proteostatic regulation are augmented by overexpressing CRTC (CREB-regulated transcriptional coactivator). Intriguingly, CRTC overexpression in muscles robustly restores protein folding and proteasomal activity in a fly Huntington’s disease (HD) model, and ameliorates HD related pathogenesis, such as protein aggregates, motility, and lifespan. Moreover, CREB activity increases during aging, and further enhances its activity can suppress protein aggregates in aged muscles. Together, our results identified CRTC/CREB downstream ROS/JNK signaling as a conserved sensor to tackle oxidative and proteotoxic stresses. Boosting CRTC/CREB activity is a potential therapeutic strategy to treat aging related protein aggregation diseases. |
| first_indexed | 2024-04-13T11:25:15Z |
| format | Article |
| id | doaj.art-6d900e51b62e40809d12f71192b0fb9c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T11:25:15Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6d900e51b62e40809d12f71192b0fb9c2022-12-22T02:48:42ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811410.1038/s41419-022-05122-yThe CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in DrosophilaYoujie Yin0Peng Ma1Saifei Wang2Yao Zhang3Ruolei Han4Chunyu Huo5Meixian Wu6Hansong Deng7Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityYangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, School of Life Sciences and Technology, Tongji UniversityAbstract cAMP Responsible Element Binding Protein (CREB) is an evolutionarily conserved transcriptional factor that regulates cell growth, synaptic plasticity and so on. In this study, we unexpectedly found proteasome inhibitors, such as MLN2238, robustly increase CREB activity in adult flies through a large-scale compound screening. Mechanistically, reactive oxidative species (ROS) generated by proteasome inhibition are required and sufficient to promote CREB activity through c-Jun N-terminal kinase (JNK). In 293 T cells, JNK activation by MLN2238 is also required for increase of CREB phosphorylation at Ser133. Meanwhile, transcriptome analysis in fly intestine identified a group of genes involved in redox and proteostatic regulation are augmented by overexpressing CRTC (CREB-regulated transcriptional coactivator). Intriguingly, CRTC overexpression in muscles robustly restores protein folding and proteasomal activity in a fly Huntington’s disease (HD) model, and ameliorates HD related pathogenesis, such as protein aggregates, motility, and lifespan. Moreover, CREB activity increases during aging, and further enhances its activity can suppress protein aggregates in aged muscles. Together, our results identified CRTC/CREB downstream ROS/JNK signaling as a conserved sensor to tackle oxidative and proteotoxic stresses. Boosting CRTC/CREB activity is a potential therapeutic strategy to treat aging related protein aggregation diseases.https://doi.org/10.1038/s41419-022-05122-y |
| spellingShingle | Youjie Yin Peng Ma Saifei Wang Yao Zhang Ruolei Han Chunyu Huo Meixian Wu Hansong Deng The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila Cell Death and Disease |
| title | The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila |
| title_full | The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila |
| title_fullStr | The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila |
| title_full_unstemmed | The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila |
| title_short | The CRTC-CREB axis functions as a transcriptional sensor to protect against proteotoxic stress in Drosophila |
| title_sort | crtc creb axis functions as a transcriptional sensor to protect against proteotoxic stress in drosophila |
| url | https://doi.org/10.1038/s41419-022-05122-y |
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