Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis
Open accessAbstract
Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of pyroptosis in comparison with necroptosis. Different from necroptosis, pyroptosis undergoes membrane blebbing and produces apoptotic body-like cell protrusions (termed pyroptotic bodies) prior to plasma membrane rupture. The rupture in necroptosis is explosion-like, whereas in pyroptosis it leads to flattening of cells. It is known that the execution of necroptosis is mediated by mixed lineage kinase domain-like (MLKL) oligomers in the plasma membrane, whereas gasdermin-D (GSDMD) mediates pyroptosis after its cleavage by caspase-1 or caspase-11. We show that N-terminal fragment of GSDMD (GSDMD-N) generated by caspase cleavage also forms oligomer and migrates to the plasma membrane to kill cells. Both MLKL and GSDMD-N are lipophilic and the N-terminal sequences of both proteins are important for their oligomerization and plasma membrane translocation. Unlike MLKL which forms channels on the plasma membrane that induces influx of selected ions which osmotically swell the cells to burst, GSDMD-N forms non-selective pores and does not rely on increased osmolarity to disrupt cells. Our study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis.
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Membrane targeting enables GSDMD-N oligomerization, generating a pore responsible for rapid plasma membrane permeabilization.
“Membrane targeting enables GSDMD-N oligomerization, generating a pore that is responsible for rapid plasma membrane permeabilization [629–633].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [632]
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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., Wang, F., & Shao, F. (2015) · Nature · doi:10.1038/nature15514 · Cited by 6,659 · see citing works
Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation
Wyllie, A. H. (1980) · Nature · doi:10.1038/284555a0 · Cited by 4,549 · see citing works
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 · see citing works
Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores
Liu, X., Zhang, Z., Ruan, J., Pan, Y., Magupalli, V. G., Wu, H., & Lieberman, J. (2016) · Nature · doi:10.1038/nature18629 · Cited by 3,202 · see citing works
Pore-forming activity and structural autoinhibition of the gasdermin family
Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., Sun, H., Wang, D.-C., & Shao, F. (2016) · Nature · doi:10.1038/nature18590 · Cited by 2,771 · see citing works
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.031 · Cited by 2,698 · see citing works
Self-citationMechanisms and Functions of Inflammasomes
Lamkanfi, M., & Dixit, V. M. (2014) · Cell · doi:10.1016/j.cell.2014.04.007 · Cited by 2,521 · see citing works
Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion
He, W.-T., Wan, H., Hu, L., Chen, P., Wang, X., Huang, Z., Yang, Z.-H., Zhong, C.-Q., & Han, J. (2015) · Cell Research · doi:10.1038/cr.2015.139 · Cited by 2,517 · see citing works
Self-citationCho, Y., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M., & Chan, F. K.-M. (2009) · Cell · doi:10.1016/j.cell.2009.05.037 · Cited by 2,435 · see citing works
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214 · see citing works
Self-citationRIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
Zhang, D.-W., Shao, J., Lin, J., Zhang, N., Lu, B.-J., Lin, S.-C., Dong, M.-Q., & Han, J. (2009) · Science · doi:10.1126/science.1172308 · Cited by 1,931 · see citing works
Self-citationProgrammed Cell Death in Animal Development and Disease
Fuchs, Y., & Steller, H. (2011) · Cell · doi:10.1016/j.cell.2011.10.033 · Cited by 1,915 · see citing works
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735 · see citing works
Wang, H., Sun, L., Su, L., Rizo, J., Liu, L., Wang, L., Wang, F., & Wang, X. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.003 · Cited by 1,564 · see citing works
Self-citationPro-inflammatory programmed cell death
Cookson, B. T., & Brennan, M. A. (2001) · Trends in Microbiology · doi:10.1016/s0966-842x(00)01936-3 · Cited by 1,422 · see citing works
Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis
Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G. (2014) · Nature Cell Biology · doi:10.1038/ncb2883 · Cited by 1,322 · see citing works
Hou, F., Sun, L., Zheng, H., Skaug, B. A., Jiang, Q., & Chen, Z. J. (2011) · Cell · doi:10.1016/j.cell.2011.06.041 · Cited by 1,274 · see citing works
Fink, S. L., & Cookson, B. T. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00751.x · Cited by 1,114 · see citing works
Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J., & Liu, Z.-G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200012109 · Cited by 901 · see citing works
GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes
Aglietti, R. A., Estevez, A., Gupta, A., Ramirez, M. G., Liu, P. S., Kayagaki, N., Ciferri, C., Dixit, V. M., & Dueber, E. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607769113 · Cited by 898 · see citing works
MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates
Dondelinger, Y., Declercq, W., Montessuit, S., Roelandt, R., Gonçalves, A. C., Bruggeman, I., Hulpiau, P., Weber, K., Sehon, C. A., Marquis, R. W., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.026 · Cited by 812 · see citing works
Chen, X., Li, W., Ren, J., Huang, D., He, W., Song, Y., Yang, C., Li, W., Zheng, X., Chen, P., et al. (2013) · Cell Research · doi:10.1038/cr.2013.171 · Cited by 778 · see citing works
Self-citationMaeno, E., Ishizaki, Y., Kanaseki, T., Hazama, A., & Okada, Y. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.140216197 · Cited by 703 · see citing works
To Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate
Green, D. R., & Levine, B. (2014) · Cell · doi:10.1016/j.cell.2014.02.049 · Cited by 687 · see citing works
Salmonella induces macrophage death by caspase‐1‐dependent necrosis
Brennan, M. A., & Cookson, B. T. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.02103.x · Cited by 674 · see citing works
Hildebrand, J. M., Tanzer, M. C., Lucet, I. S., Young, S. N., Spall, S. K., Sharma, P., Pierotti, C., Garnier, J.-M., Dobson, R. C. J., Webb, A. I., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408987111 · Cited by 598 · see citing works
Programmed necrosis in inflammation: Toward identification of the effector molecules
Wallach, D., Kang, T., Dillon, C. P., & Green, D. R. (2016) · Science · doi:10.1126/science.aaf2154 · Cited by 547 · see citing works
Cell death in the host response to infection
Labbè, K., & Saleh, M. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.91 · Cited by 388 · see citing works
Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis
Rodríguez, D. A., Weinlich, R., Brown, S., Guy, C. S., Fitzgerald, P., Dillon, C. P., Oberst, A., Quarato, G., Low, J. A., Cripps, J. G., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.70 · Cited by 379 · see citing works
Programmed Necrosis in the Cross Talk of Cell Death and Inflammation
Chan, F. K.-M., Luz, N. F., & Moriwaki, K. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112248 · Cited by 350 · see citing works
Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis
Wu, X.-N., Yang, Z.-H., Wang, X.-K., Zhang, Y., Wan, H., Song, Y., Chen, X., Shao, J., & Han, J. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.77 · Cited by 299 · see citing works
Self-citationChen, W., Zhou, Z., Li, L., Zhong, C., Zheng, X., Wu, X., Zhang, Y., Ma, H., Huang, D., Li, W., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.435545 · Cited by 265 · see citing works
Self-citationSequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis
Quarato, G., Guy, C. S., Grace, C. R., Llambi, F., Nourse, A., Rodríguez, D. A., Wakefield, R., Frase, S., Moldoveanu, T., & Green, D. R. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.01.011 · Cited by 242 · see citing works
Xia, B., Fang, S., Chen, X., Hu, H., Chen, P., Wang, H., & Gao, Z. (2016) · Cell Research · doi:10.1038/cr.2016.26 · Cited by 202 · see citing works
Self-citationMechanisms of unconventional secretion of IL-1 family cytokines
Monteleone, M. M., Stow, J. L., & Schroder, K. (2015) · Cytokine · doi:10.1016/j.cyto.2015.03.022 · Cited by 135 · see citing works
Reese, A. L., & Kavalali, E. T. (2015) · eLife · doi:10.7554/elife.09262 · Cited by 78 · see citing works
Shiokawa, D., Maruta, H., & Tanuma, S.-I. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00887-9 · Cited by 59 · see citing works
Channels and Volume Changes in the Life and Death of the Cell
Pasantes‐Morales, H. (2016) · Molecular Pharmacology · doi:10.1124/mol.116.104158 · Cited by 57 · see citing works
The Detection of Ionophorous Antibiotic-Cation Complexes in Water with Fluorescent Probes
Feinstein, M. B., & Felsenfeld, H. (1971) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.68.9.2037 · Cited by 52 · see citing works
ANG-2 for quantitative Na+ determination in living cells by time-resolved fluorescence microscopy
Roder, P., & Hille, C. (2014) · Photochemical & Photobiological Sciences · doi:10.1039/c4pp00061g · Cited by 42 · see citing works
A potassium ionophore (Nigericin) inhibits stimulation of human lymphocytes by mitogens.
Daniele, R. P., Holian, S. K., & Nowell̀, P. C. (1978) · The Journal of Experimental Medicine · doi:10.1084/jem.147.2.571 · Cited by 26 · see citing works
A novel method for measuring intracellular pH and potassium concentration
Bashford, C. L., Alder, G. M., Micklem, K., et al. (1983) · Bioscience Reports · doi:10.1007/bf01172873 · Cited by 25 · see citing works
Wide field fluorescent imaging of extracellular spatiotemporal potassium dynamics in vivo
Bazzigaluppi, P., Dufour, S., & Carlen, P. L. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.10.012 · Cited by 18 · see citing works
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- Authors
- Chen, X., He, W.-T., Hu, L., Li, J., Fang, Y., Wang, X., Xu, X., Wang, Z., Huang, K., & Han, J.
- Affiliations
- Xiamen University (CN)
- Corresponding author
- Han, Jiahuai
- ORCID
- Venue
- Cell Research
- Published
- 2016-08-30
- Volume
- 26
- Issue
- 9
- Pages
- 1007-1020
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC5034106
- OpenAlex
- W2517997111
- Cited by
- 831
- References
- 43
- Citations by year
- 2026: 58 · 2025: 102 · 2024: 132 · 2023: 137 · 2022: 123 · 2021: 88 · 2020: 59 · 2019: 47 · 2018: 49 · 2017: 33 · 2016: 2
- FWCI
- 22.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2015CB553800, 111 Project, 31420103910, 973 Program, J1310027, 2014CB541804, 31330047, 91029304, B12001)
- Higher Education Discipline Innovation Project (B12001)
- National Key Research and Development Program of China (2014CB541804, J1310027, 2015CB553800, 2013CB944903, 91029304)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- pyroptosis, necroptosis, gasdermin D, MLKL, GSDMD-N, plasma membrane rupture, membrane blebbing, programmed cell death, caspase-1, caspase-11, protein oligomerization, membrane translocation, cell morphology
- MeSH terms
- Pyroptosis, Gasdermins, Amino Acids, Animals, Cell Line, Cell Membrane, Cell Membrane Permeability, Humans, Necrosis, Neoplasm Proteins, Protein Kinases, Structure-Activity Relationship, Protein Transport, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Cell Shape, Apoptosis Regulatory Proteins, Protein Multimerization
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