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

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.

Pyroptosis: A promising therapeutic target for noninfectious diseases

“… 31 Interestingly, caspase‐8 can also shear gasdermin C (GSDMC) into GDSMC NT fragments and subsequently switch apoptosis to pyroptosis in breast cancer cells with TNF‐α treatment. 32 Consistently, Zhang et al 33 recently showed that the caspase‐8, which is recruited to ROS‐oxidized and internalized death receptor 6 (DR6) after application with dimethyl‐α‐ketoglutarate (DM‐α‐KG), can cleave GSDMC at Asp240 and subsequently trigger GSDMC‐mediated pyroptotic cell death in many human gastric cancer cells (SGC‐7901 and BGC‐823), human colon cancer cells (HCT116) and human hepatoma cells (Huh7).…”

“…Chemotherapeutics, such as doxorubicin, lobaplatin, cisplatin and tetraarsenic hexoxide, can suppress the growth of neuroblastoma, melanoma, colon cancer cells and breast cancer by inducing GSDME‐mediated pyroptosis. 85 , 86 , 87 , 88 Recently, Zhang et al 33 showed that intratumoral injection of DM‐αKG can notably repress tumour growth and metastasis through caspase‐8‐GSDMC‐mediated pyroptosis. Moreover, GSDME/GSDMB‐dependent pyroptosis is implicated in cytotoxic T lymphocytes or chimeric antigen receptor (CAR) T cell‐mediated antitumour immunity.…”

Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury

“…GSDMC is primarily cleaved by Caspase-8 (Hou, Zhao et al 2020, Zhang, Zhou et al 2021). Indeed, the pattern of bands of cleaved GSDMC-2/-3 is compatible with the activity of Caspase-8 (Julien and Wells 2017).…”

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

“…Hepatic NOD2, a well-characterized intracellular PRR of the NOD-like receptor (NLR) family, has been shown to promote hepatocarcinogenesis [ 41 ]. In addition, GSDMC, metabolized by α -ketoglutarate and mediated through caspase-8, results in pyroptosis [ 42 ]. Overall, increasing studies have confirmed the roles of these genes (DHX9, CHMP4B, BAK1, NOD2, and GSDMC) in HCC.…”