Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Nat Commun. 2021 Nov 3;12(1):6321. doi: 10.1038/s41467-021-26653-6.
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.
多能转录因子 SOX2 对于神经胶质瘤干细胞（GSC）的维持至关重要，这些细胞被认为是肿瘤生长、治疗耐药和复发的根源。为了了解 SOX2 在 GSCs 中的调控机制，我们利用蛋白质组学方法鉴定出 E3 泛素连接酶 TRIM26 是 SOX2 的直接相互作用蛋白。出乎意料的是，我们发现 TRIM26 耗竭会降低 SOX2 蛋白水平，并增加患者来源的 GSCs 中 SOX2 的多泛素化，表明 TRIM26 促进 SOX2 蛋白稳定性。因此，TRIM26 的敲低会破坏 SOX2 基因网络，并抑制多种 GSC 系的自我更新能力和体内致瘤性。在机制上，我们发现 TRIM26 通过其 C 端 PRYSPRY 结构域，但不依赖其 RING 结构域，通过直接抑制 SOX2 与 WWP2 的相互作用来稳定 SOX2 蛋白，我们将其鉴定为 GSCs 中 SOX2 的真正 E3 连接酶。我们的工作确定了 E3 连接酶竞争是 SOX2 调控的一个关键机制，对 GSC 特性和维持具有功能后果。
