美国德克萨斯大学安德森癌症中心Boyi Gan和Junjie Chen共同合作，近期取得重要工作进展。他们研究发现肌动蛋白细胞骨架对二硫胁迫的易损性可以介导双硫死亡。相关研究成果2023年2月6日在线发表于《自然—细胞生物学》杂志上。

据介绍，SLC7A11介导的胱氨酸摄取抑制铁死亡，但在葡萄糖饥饿的条件下促进细胞死亡，后者细胞死亡的机制特征尚不清楚。

研究人员表明，在葡萄糖饥饿下SLC7A11^high细胞内二硫化物的异常积累诱导了一种以前未被表征的细胞死亡形式，与凋亡和铁下垂不同。我们称这种细胞死亡为双硫死亡。化学蛋白质组学和细胞生物学分析表明，在SLC7A11^high细胞中，葡萄糖饥饿诱导肌动蛋白细胞骨架蛋白中的异常二硫键，F-actin以SLC7A11-依赖的方式瓦解。CRISPR筛选和功能研究表明，WAVE调节复合物（促进肌动蛋白聚合和板状伪足形成）的失活抑制了双硫死亡，而Rac的组成性激活促进了双硫死亡。研究人员进一步表明，葡萄糖转运蛋白抑制剂在SLC7A11^high癌症细胞中诱导双硫死亡，并抑制SLC7A1^high肿瘤细胞的生长。

总之，研究结果表明，肌动蛋白细胞骨架对二硫键应激的敏感性介导了双硫死亡，并提出了一种在癌症治疗中针对双硫死亡的治疗策略。

附：英文原文

Title: Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis

Author: Liu, Xiaoguang, Nie, Litong, Zhang, Yilei, Yan, Yuelong, Wang, Chao, Colic, Medina, Olszewski, Kellen, Horbath, Amber, Chen, Xiong, Lei, Guang, Mao, Chao, Wu, Shiqi, Zhuang, Li, Poyurovsky, Masha V., James You, M., Hart, Traver, Billadeau, Daniel D., Chen, Junjie, Gan, Boyi

Issue&Volume: 2023-02-06

Abstract: SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.

DOI: 10.1038/s41556-023-01091-2

Source: https://www.nature.com/articles/s41556-023-01091-2