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

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.

• Authors: 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, Albert H Kim
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6321 (11 03 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34732716 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• SOX2 protein, human
• SOXB1 Transcription Factors
• Tripartite Motif Proteins
• WWP2 protein, human
• TRIM26 protein, human
• Ubiquitin-Protein Ligases

Topics

• Animals
• B30.2-SPRY Domain
• Binding, Competitive (genetics, physiology)
• Brain Neoplasms (genetics)
• Female
• Gene Knockdown Techniques
• Glioblastoma (genetics, metabolism)
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Proteomics
• SOXB1 Transcription Factors (genetics, metabolism)
• Tripartite Motif Proteins (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination