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The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination
MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192928/ https://www.ncbi.nlm.nih.gov/pubmed/37028761 http://dx.doi.org/10.1016/j.jbc.2023.104675 |
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author | Zhang, Zubin Li, Mei Lin, Peng Ren, Ying He, Yuanming Wang, Siyu Xu, Yujia Cao, Biyin Wang, Guanghui Moran, Michael F. Mao, Xinliang |
author_facet | Zhang, Zubin Li, Mei Lin, Peng Ren, Ying He, Yuanming Wang, Siyu Xu, Yujia Cao, Biyin Wang, Guanghui Moran, Michael F. Mao, Xinliang |
author_sort | Zhang, Zubin |
collection | PubMed |
description | MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3β (GSK3β). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling, but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3β inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3β/MafA for the treatment of MM. |
format | Online Article Text |
id | pubmed-10192928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-101929282023-05-19 The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination Zhang, Zubin Li, Mei Lin, Peng Ren, Ying He, Yuanming Wang, Siyu Xu, Yujia Cao, Biyin Wang, Guanghui Moran, Michael F. Mao, Xinliang J Biol Chem Research Article MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3β (GSK3β). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling, but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3β inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3β/MafA for the treatment of MM. American Society for Biochemistry and Molecular Biology 2023-04-05 /pmc/articles/PMC10192928/ /pubmed/37028761 http://dx.doi.org/10.1016/j.jbc.2023.104675 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Zhang, Zubin Li, Mei Lin, Peng Ren, Ying He, Yuanming Wang, Siyu Xu, Yujia Cao, Biyin Wang, Guanghui Moran, Michael F. Mao, Xinliang The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title | The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title_full | The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title_fullStr | The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title_full_unstemmed | The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title_short | The ubiquitin ligase HERC4 suppresses MafA transcriptional activity triggered by GSK3β in myeloma by atypical K63-linked polyubiquitination |
title_sort | ubiquitin ligase herc4 suppresses mafa transcriptional activity triggered by gsk3β in myeloma by atypical k63-linked polyubiquitination |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192928/ https://www.ncbi.nlm.nih.gov/pubmed/37028761 http://dx.doi.org/10.1016/j.jbc.2023.104675 |
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