1. Academic Validation
  2. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8

The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8

  • Cell Res. 2021 Sep;31(9):980-997. doi: 10.1038/s41422-021-00506-9.
Jia-Yuan Zhang  # 1 Bo Zhou  # 1 Ru-Yue Sun  # 1 Yuan-Li Ai  # 1 Kang Cheng 1 Fu-Nan Li 2 Bao-Rui Wang 2 Fan-Jian Liu 1 Zhi-Hong Jiang 1 Wei-Jia Wang 1 Dawang Zhou 1 Hang-Zi Chen 3 Qiao Wu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2 School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
  • 3 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. Chenhz@xmu.edu.cn.
  • 4 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. qiaow@xmu.edu.cn.
  • # Contributed equally.
Abstract

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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