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

Tatenda Mahlokozera, Bhuvic Patel, Hao Chen, Patrick Desouza, Xuan Qu, Diane D. Mao, Daniel Hafez, Wei Yang, Rukayat Taiwo, Mounica Paturu, Afshin Salehi, Amit D. Gujar, Gavin P. Dunn, Nima Mosammaparast, Allegra A. Petti, Hiroko Yano () and Albert H. Kim ()
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Tatenda Mahlokozera: Washington University School of Medicine
Bhuvic Patel: Washington University School of Medicine
Hao Chen: Washington University School of Medicine
Patrick Desouza: Washington University School of Medicine
Xuan Qu: Washington University School of Medicine
Diane D. Mao: Washington University School of Medicine
Daniel Hafez: Washington University School of Medicine
Wei Yang: Washington University School of Medicine
Rukayat Taiwo: Washington University School of Medicine
Mounica Paturu: Washington University School of Medicine
Afshin Salehi: Washington University School of Medicine
Amit D. Gujar: Washington University School of Medicine
Gavin P. Dunn: Washington University School of Medicine
Nima Mosammaparast: Washington University School of Medicine
Allegra A. Petti: Washington University School of Medicine
Hiroko Yano: Washington University School of Medicine
Albert H. Kim: Washington University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26653-6

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