Volume 31, No 9, Sep 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 9, September 2021: 980-997   |  Open Access

ORIGINAL ARTICLES

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

Jia-yuan Zhang¹ , Bo Zhou¹ , Ru-yue Sun¹ , Yuan-li Ai¹ , Kang Cheng¹ , Fu-nan Li² , Bao-rui Wang² , Fan-jian Liu¹ , Zhi-hong Jiang¹ , Wei-jia Wang¹ , Dawang Zhou¹ , Hang-zi Chen^1,* , Qiao Wu^1,*

¹State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
²School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
These authors contributed equally: Jia-yuan Zhang, Bo Zhou, Ru-yue Sun, Yuan-li Ai Correspondence: Hang-zi Chen(Chenhz@xmu.edu.cn)Qiao Wu(qiaow@xmu.edu.cn)

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.

https://doi.org/10.1038/s41422-021-00506-9

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