Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes
The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resist...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/103401 http://hdl.handle.net/10220/47309 |
| _version_ | 1826112311827365888 |
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| author | Wong, Daphne Pei Wen Ng, Mei Ying Leung, Jia Yu Boh, Boon Kim Lim, Ee Chien Tan, Shi Hua Lim, Shuying Seah, Wen Hui Hu, Christine Zhiwen Ho, Boon Chuan Ng, Daphne Hui Ping Hagen, Thilo |
| author2 | Massiah, Michael |
| author_facet | Massiah, Michael Wong, Daphne Pei Wen Ng, Mei Ying Leung, Jia Yu Boh, Boon Kim Lim, Ee Chien Tan, Shi Hua Lim, Shuying Seah, Wen Hui Hu, Christine Zhiwen Ho, Boon Chuan Ng, Daphne Hui Ping Hagen, Thilo |
| author_sort | Wong, Daphne Pei Wen |
| collection | NTU |
| description | The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds. |
| first_indexed | 2024-10-01T03:04:55Z |
| format | Journal Article |
| id | ntu-10356/103401 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:04:55Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1034012020-03-07T11:45:55Z Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes Wong, Daphne Pei Wen Ng, Mei Ying Leung, Jia Yu Boh, Boon Kim Lim, Ee Chien Tan, Shi Hua Lim, Shuying Seah, Wen Hui Hu, Christine Zhiwen Ho, Boon Chuan Ng, Daphne Hui Ping Hagen, Thilo Massiah, Michael School of Civil and Environmental Engineering Andrographolide DRNTU::Engineering::Environmental engineering NRF2 The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds. Published version 2019-01-02T07:00:30Z 2019-12-06T21:11:51Z 2019-01-02T07:00:30Z 2019-12-06T21:11:51Z 2018 Journal Article Wong, D. P. W., Ng, M. Y., Leung, J. Y., Boh, B. K., Lim, E. C., Tan, S. H., . . . Hagen, T. (2018). Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes. PLOS ONE, 13(10), e0204853-. doi:10.1371/journal.pone.0204853 https://hdl.handle.net/10356/103401 http://hdl.handle.net/10220/47309 10.1371/journal.pone.0204853 en PLOS ONE © 2018 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 17 p. application/pdf |
| spellingShingle | Andrographolide DRNTU::Engineering::Environmental engineering NRF2 Wong, Daphne Pei Wen Ng, Mei Ying Leung, Jia Yu Boh, Boon Kim Lim, Ee Chien Tan, Shi Hua Lim, Shuying Seah, Wen Hui Hu, Christine Zhiwen Ho, Boon Chuan Ng, Daphne Hui Ping Hagen, Thilo Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title_full | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title_fullStr | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title_full_unstemmed | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title_short | Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes |
| title_sort | regulation of the nrf2 transcription factor by andrographolide and organic extracts from plant endophytes |
| topic | Andrographolide DRNTU::Engineering::Environmental engineering NRF2 |
| url | https://hdl.handle.net/10356/103401 http://hdl.handle.net/10220/47309 |
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