HECT 型 E3 泛素 WWP1（也称为 NEDD4 样 E3 泛素蛋白连接酶 WWP1）在急性髓系白血病 (AML) 细胞中充当致癌因子。 AML 中的 WWP1 过度表达赋予白血病母细胞（异常的未成熟白细胞）增殖优势，并抵消细胞凋亡和分化。为了阐明 WWP1 致癌活性的分子基础，我们发现 WWP1 是 AML 细胞中硫氧还蛋白相互作用蛋白 (TXNIP) 介导的活性氧 (ROS) 产生的先前未知的负调节因子。 TXNIP 抑制硫氧还蛋白 (Trx) 的二硫键还原酶活性，损害其抗氧化功能，最终导致细胞氧化还原稳态破坏。此外，TXNIP 通过阻断葡萄糖摄取和代谢来限制细胞生长和存活。在这里，我们发现WWP1直接与TXNIP相互作用，从而促进其泛素依赖性蛋白酶体蛋白水解。因此，在 AML 母细胞中，响应 WWP1 失活而积累的 TXNIP 会降低 Trx 活性并增加 ROS 产生，从而诱导细胞氧化应激。 WWP1 耗尽的细胞中 ROS 生成增加，最终导致 DNA 链断裂和随后的细胞凋亡。与 WWP1 失活后 TXNIP 稳定一致，我们还观察到葡萄糖摄取和消耗均受到损害。因此，在 WWP1 耗尽的细胞中观察到的细胞死亡增加也可能是由于 TXNIP 积累导致的葡萄糖摄取和糖酵解通量的减弱所致。未来的研究需要确定 WWP1 过度表达的原始细胞中 TXNIP 依赖​​性的氧化还原稳态失调是否可能影响白血病细胞对化疗药物的反应。© 2024 作者。约翰·威利出版的《分子肿瘤学》

The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin-dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1-depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up-take and consumption. Hence, a contribution to the increased cell death observed in WWP1-depleted cells also possibly arises from the attenuation of glucose up-take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP-dependent deregulation of redox homeostasis in WWP1-overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.