In:
Cell Research, Springer Science and Business Media LLC, Vol. 31, No. 9 ( 2021-09), p. 980-997
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.
Type of Medium:
Online Resource
ISSN:
1001-0602
,
1748-7838
DOI:
10.1038/s41422-021-00506-9
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2082402-6
SSG:
12
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