The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8
Open accessAbstract
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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Cites
1 retracted
RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M. (2009) · Nature · doi:10.1038/nature07767 · Cited by 992
RetractedCancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Kayagaki, N., Stowe, I. B., Lee, B. L., O’Rourke, K., Anderson, K., Warming, S., Cuellar, T., Haley, B., Roose-Girma, M., Phung, Q. T., et al. (2015) · Nature · doi:10.1038/nature15541 · Cited by 3,686
Self-citationChemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., Wang, K., & Shao, F. (2017) · Nature · doi:10.1038/nature22393 · Cited by 3,199
Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death
Shi, J., Gao, W., & Shao, F. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.10.004 · Cited by 3,088
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Self-citationFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
The gasdermins, a protein family executing cell death and inflammation
Broz, P., Pelegrín, P., & Shao, F. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0228-2 · Cited by 1,641
Rogers, C., Fernandes-Alnemri, T., Mayes, L., Alnemri, D., Cingolani, G., & Alnemri, E. S. (2017) · Nature Communications · doi:10.1038/ncomms14128 · Cited by 1,510 · cited 1×
“For example, inflammasomeactivated caspase-1/4/5/11 cleave GSDMD to produce an Nterminal fragment that triggers pyroptosis, while proapoptotic stimuli activate caspase-3, which cleaves GSDME to induce pyroptosis.(5,6)”
BackgroundGranzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells
Zhou, Z., He, H., Wang, K., Shi, X., Wang, Y., Su, Y., Wang, Y., Li, D., Liu, W., Zhang, Y., et al. (2020) · Science · doi:10.1126/science.aaz7548 · Cited by 1,317
Cited by
Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Peng, F., Liao, M., Qin, R., Zhu, S., Peng, C., Fu, L., Chen, Y., & Han, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01110-y · Cited by 832
Pyroptosis in inflammatory diseases and cancer
Rao, Z., Zhu, Y., Yang, P., Chen, Z., Xia, Y., Qiao, C., Liu, W., Deng, H., Li, J., Ning, P., et al. (2022) · Theranostics · doi:10.7150/thno.71086 · Cited by 800
Role of pyroptosis in inflammation and cancer
Wei, X., Xie, F., Zhou, X., Wu, Y., Yan, H., Liu, T., Huang, J., Wang, F., Zhou, F., & Zhang, L. (2022) · Cellular & Molecular Immunology · doi:10.1038/s41423-022-00905-x · Cited by 699
Hsu, S.-K., Li, C.-Y., Lin, I.-L., Syue, W.-J., Chen, Y.-F., Cheng, K.-C., Teng, Y.-N., Lin, Y.-H., Yen, C.-H., & Chiu, C.-C. (2021) · Theranostics · doi:10.7150/thno.62521 · Cited by 484
Self-citationPyroptosis-Induced Inflammation and Tissue Damage
Vasudevan, S. O., Behl, B., & Rathinam, V. A. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101781 · Cited by 412
Metadata
- Authors
- Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., Jiang, Z.-H., Wang, W.-J., Zhou, D., Chen, H.-Z., & Wu, Q.
- Venue
- Cell Research
- Published
- 2021-05-19
- Volume
- 31
- Issue
- 9
- Pages
- 980-997
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- OpenAlex
- W3163560329
- Cited by
- 392
- References
- 17
- FWCI
- 15.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., Jiang, Z.-H., Wang, W.-J., Zhou, D., Chen, H.-Z., & Wu, Q. (2021). The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Research. https://doi.org/10.1038/s41422-021-00506-9
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