Key Points The citric acid cycle metabolite fumarate upregulates ULBP2/5 surface expression. A high fumarate level induces redox changes, resulting in ROS production. ROS production by fumarate associates with ULBP2/5 surface expression. Visual Abstract Fumarate is a tricarboxylic acid cycle metabolite whose intracellular accumulation is linked to inflammatory signaling and development of cancer. In this study, we demonstrate that endogenous fumarate accumulation upregulates surface expression of the immune stimulatory NK group 2, member D (NKG2D) ligands ULBP2 and ULBP5. In agreement with this, accumulation of fumarate by the therapeutic drug dimethyl fumarate (DMF) also promotes ULBP2/5 surface expression. Mechanistically, we found that the increased ULBP2/5 expression was dependent on oxidative stress and the antioxidants N-acetylcysteine and glutathione (GSH) abrogated ULBP2/5 upregulated by DMF. Fumarate can complex with GSH and thereby exhaust cells of functional GSH capacity. In line with this, inhibition of GSH reductase (GR), the enzyme responsible for GSH recycling, promoted ULBP2/5 surface expression. Loss of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) associates with a malignant form of renal cancer characterized by fumarate accumulation and increased production of reactive oxygen species, highlighting fumarate as an oncometabolite. Interestingly, FH-deficient renal cancer cells had low surface expression of ULBP2/5 and were unresponsive to DMF treatment, suggesting that the fumarate-stimulating ULBP2/5 pathway is abrogated in these cells as an immune-evasive strategy. Together, our data show that ULBP2/5 expression can be upregulated by accumulation of fumarate, likely by depleting cells of GSH antioxidant capacity. Given that DMF is an approved human therapeutic drug, our findings support a broader use of DMF in treatment of cancers and inflammatory conditions.

中文翻译：

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富马酸盐通过清除谷胱甘肽抗氧化能力上调 ULBP2/ULBP5 的表面表达

要点 柠檬酸循环代谢物富马酸盐上调 ULBP2/5 表面表达。高富马酸盐水平诱导氧化还原变化，导致 ROS 产生。富马酸盐产生的 ROS 与 ULBP2/5 表面表达有关。Visual Abstract Fumarate 是一种三羧酸循环代谢物，其细胞内积累与炎症信号传导和癌症的发展有关。在这项研究中，我们证明内源性富马酸盐积累上调免疫刺激性 NK 组 2、成员 D (NKG2D) 配体 ULBP2 和 ULBP5 的表面表达。与此一致，治疗药物富马酸二甲酯 (DMF) 积累的富马酸也促进了 ULBP2/5 表面表达。从机制上讲，我们发现增加的 ULBP2/5 表达依赖于氧化应激，抗氧化剂 N-乙酰半胱氨酸和谷胱甘肽 (GSH) 消除了 DMF 上调的 ULBP2/5。富马酸盐可与 GSH 复合，从而耗尽具有功能性 GSH 容量的细胞。与此一致的是，抑制 GSH 还原酶 (GR)（负责 GSH 回收的酶）促进了 ULBP2/5 表面表达。三羧酸循环酶延胡索酸水合酶 (FH) 的缺失与以延胡索酸积累和活性氧产生增加为特征的肾癌恶性形式有关，突出了延胡索酸作为癌代谢物的作用。有趣的是，FH 缺陷的肾癌细胞具有 ULBP2/5 的低表面表达并且对 DMF 治疗无反应，表明富马酸盐刺激 ULBP2/5 通路在这些细胞中被废除，作为一种免疫逃避策略。总之，我们的数据表明 ULBP2/5 表达可以通过富马酸盐的积累上调，可能是通过消耗 GSH 抗氧化能力的细胞。鉴于 DMF 是一种获批的人类治疗药物，我们的研究结果支持更广泛地使用 DMF 治疗癌症和炎症。