上睑下垂
内吞作用
细胞生物学
程序性细胞死亡
半胱氨酸蛋白酶
生物
细胞凋亡
代谢物
劈理(地质)
受体
癌症研究
生物化学
断裂(地质)
古生物学
作者
Jia-yuan Zhang,Bo Zhou,Ru-yue Sun,Yuan-li Ai,Kang Cheng,Fu-Nan Li,Bao-rui Wang,Fan-jian Liu,Zhihong Jiang,Weijia Wang,Dawang Zhou,Hang-zi Chen,Qiao Wu
出处
期刊:Cell Research
[Springer Nature]
日期:2021-05-19
卷期号:31 (9): 980-997
被引量:150
标识
DOI:10.1038/s41422-021-00506-9
摘要
Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.
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