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Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquiti...

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Autores principales: Mahlokozera, Tatenda, Patel, Bhuvic, Chen, Hao, Desouza, Patrick, Qu, Xuan, Mao, Diane D., Hafez, Daniel, Yang, Wei, Taiwo, Rukayat, Paturu, Mounica, Salehi, Afshin, Gujar, Amit D., Dunn, Gavin P., Mosammaparast, Nima, Petti, Allegra A., Yano, Hiroko, Kim, Albert H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566473/
https://www.ncbi.nlm.nih.gov/pubmed/34732716
http://dx.doi.org/10.1038/s41467-021-26653-6
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author Mahlokozera, Tatenda
Patel, Bhuvic
Chen, Hao
Desouza, Patrick
Qu, Xuan
Mao, Diane D.
Hafez, Daniel
Yang, Wei
Taiwo, Rukayat
Paturu, Mounica
Salehi, Afshin
Gujar, Amit D.
Dunn, Gavin P.
Mosammaparast, Nima
Petti, Allegra A.
Yano, Hiroko
Kim, Albert H.
author_facet Mahlokozera, Tatenda
Patel, Bhuvic
Chen, Hao
Desouza, Patrick
Qu, Xuan
Mao, Diane D.
Hafez, Daniel
Yang, Wei
Taiwo, Rukayat
Paturu, Mounica
Salehi, Afshin
Gujar, Amit D.
Dunn, Gavin P.
Mosammaparast, Nima
Petti, Allegra A.
Yano, Hiroko
Kim, Albert H.
author_sort Mahlokozera, Tatenda
collection PubMed
description The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.
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spelling pubmed-85664732021-11-19 Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma Mahlokozera, Tatenda Patel, Bhuvic Chen, Hao Desouza, Patrick Qu, Xuan Mao, Diane D. Hafez, Daniel Yang, Wei Taiwo, Rukayat Paturu, Mounica Salehi, Afshin Gujar, Amit D. Dunn, Gavin P. Mosammaparast, Nima Petti, Allegra A. Yano, Hiroko Kim, Albert H. Nat Commun Article The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance. Nature Publishing Group UK 2021-11-03 /pmc/articles/PMC8566473/ /pubmed/34732716 http://dx.doi.org/10.1038/s41467-021-26653-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mahlokozera, Tatenda
Patel, Bhuvic
Chen, Hao
Desouza, Patrick
Qu, Xuan
Mao, Diane D.
Hafez, Daniel
Yang, Wei
Taiwo, Rukayat
Paturu, Mounica
Salehi, Afshin
Gujar, Amit D.
Dunn, Gavin P.
Mosammaparast, Nima
Petti, Allegra A.
Yano, Hiroko
Kim, Albert H.
Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title_full Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title_fullStr Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title_full_unstemmed Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title_short Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
title_sort competitive binding of e3 ligases trim26 and wwp2 controls sox2 in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566473/
https://www.ncbi.nlm.nih.gov/pubmed/34732716
http://dx.doi.org/10.1038/s41467-021-26653-6
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