【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
【机 构】
：
State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen,Fuj
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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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