Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex
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Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.
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CASP8 maturation involves a cascade initiated by binding of CASP8 to FADD at DISC.
“In particular, CASP8 maturation involves a cascade of events initiated by the binding of CASP8 to FADD at the DISC.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [291]
Binding of CASP8 to FADD enables assembly of a linear filament of CASP8 molecules that facilitates homodimerization and activation by autoproteolytic cleavage.
“This interaction enables the assembly of a linear filament of CASP8 molecules (depending on their DEDs) that facilitates homodimerization and consequent activation by autoproteolytic cleavage [291–295].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [291]
Cites
SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information
Biasini, M., Bienert, S., Waterhouse, A. M., Arnold, K., Studer, G., Schmidt, T., Kiefer, F., Cassarino, T. G., Bertoni, M., Bordoli, L., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku340 · Cited by 4,621 · see citing works
The TNF and TNF Receptor Superfamilies
Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00237-9 · Cited by 3,650 · see citing works
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Micheau, O., & Tschopp, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00521-x · Cited by 2,738 · see citing works
AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC
Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D. R., Latz, E., & Fitzgerald, K. A. (2009) · Nature · doi:10.1038/nature07725 · Cited by 2,627 · see citing works
Kischkel, F. C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P. H., & Peter, M. E. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00245.x · Cited by 2,181 · see citing works
Unified Polymerization Mechanism for the Assembly of ASC-Dependent Inflammasomes
Lu, A., Magupalli, V. G., Ruan, J., Yin, Q., Atianand, M. K., Vos, M. R., Schröder, G. F., Fitzgerald, K. A., Wu, H., & Egelman, E. H. (2014) · Cell · doi:10.1016/j.cell.2014.02.008 · Cited by 1,353 · see citing works
Self-citationHelical Assembly in the MyD88-IRAK4-IRAK2 Complex in TLR/IL-1R Signalling
Lin, S.-C., Lo, Y.-C., & Wu, H. (2010) · Nature · doi:10.1038/nature09121 · Cited by 1,111 · see citing works
Self-citationThe many roles of FAS receptor signaling in the immune system
Strasser, A., Jost, P. J., & Nagata, S. (2009) · Immunity · doi:10.1016/j.immuni.2009.01.001 · Cited by 968 · see citing works
A Unified Model for Apical Caspase Activation
Boatright, K. M., Renatus, M., Scott, F. L., Sperandio, S., Shin, H., Pedersen, I. M., Ricci, J., Edris, W. A., Sutherlin, D. P., Green, D. R., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00051-0 · Cited by 963 · see citing works
Feoktistova, M., Geserick, P., Kellert, B., Panayotova‐Dimitrova, D., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Häcker, G. A., & Leverkus, M. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.011 · Cited by 855 · see citing works
Tenev, T., Bianchi, K., Darding, M., Broemer, M., Langlais, C., Wållberg, F., Zachariou, A., Lopez, J. S., MacFarlane, M., Cain, K., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.006 · Cited by 818 · see citing works
Inhibition of Fas death signals by FLIPs
Tschopp, J., Irmler, M., & Thome, M. (1998) · Current Opinion in Immunology · doi:10.1016/s0952-7915(98)80223-9 · Cited by 527 · see citing works
AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC
Sagulenko, V., Thygesen, S. J., Sester, D. P., Idris, A., Cridland, J. A., Vajjhala, P. R., Roberts, T. L., Schroder, K., Vince, J. E., Hill, J. M., et al. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.37 · Cited by 511 · see citing works
Self-citationHoller, N., Tardivel, A., Kovacsovics-Bankowski, M., Hertig, S., Gaide, O., Martinon, F., Tinel, A., Deperthes, D., Calderara, S., Schulthess, T., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1428-1440.2003 · Cited by 406 · see citing works
The X-ray structure of a growth hormone–prolactin receptor complex
Somers, W. S., Ultsch, M. H., de Vos, A. M., & Kossiakoff, A. A. (1994) · Nature · doi:10.1038/372478a0 · Cited by 393 · see citing works
Dickens, L. S., Boyd, R. S., Jukes-Jones, R., Hughes, M. A., Robinson, G. L., Fairall, L., Schwabe, J. W. R., Cain, K., & MacFarlane, M. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.004 · Cited by 349 · see citing works
Park, H. H., Logette, E., Raunser, S., Cuenin, S., Walz, T., Tschopp, J., & Wu, H. (2007) · Cell · doi:10.1016/j.cell.2007.01.019 · Cited by 280 · see citing works
Self-citationThe Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations
Wang, L., Yang, J. K., Kabaleeswaran, V., Rice, A. J., Cruz, A. C., Park, A. Y., Yin, Q., Damko, E., Jang, S. B., Raunser, S., et al. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1920 · Cited by 276 · see citing works
Self-citationHughes, M. A., Powley, I. R., Jukes-Jones, R., Horn, S., Feoktistova, M., Fairall, L., Schwabe, J. W. R., Leverkus, M., Cain, K., & MacFarlane, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.023 · Cited by 257 · see citing works
(2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.x0001-0 · Cited by 257 · see citing works
Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I
Wu, B., Peisley, A., Tetrault, D. G., Li, Z., Egelman, E. H., Magor, K. E., Walz, T., Penczek, P. A., & Hur, S. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.010 · Cited by 246 · see citing works
Self-citationNMR structure and mutagenesis of the FADD (Mort1) death-effector domain
Eberstadt, M., Huang, B., Chen, Z., Meadows, R. P., Ng, S., Zheng, L., Lenardo, M. J., & Fesik, S. W. (1998) · Nature · doi:10.1038/31972 · Cited by 239 · see citing works
Death-effector Filaments: Novel Cytoplasmic Structures that Recruit Caspases and Trigger Apoptosis
Siegel, R. M., Martin, D. A., Zheng, L., Ng, S. Y., Bertin, J., Cohen, J. I., & Lenardo, M. J. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.5.1243 · Cited by 235 · see citing works
Self-citationPop, C., Oberst, A., Drąg, M., van Raam, B. J., Riedl, S. J., Green, D. R., & Salvesen, G. S. (2011) · Biochemical Journal · doi:10.1042/bj20101738 · Cited by 225 · see citing works
Structural mechanisms of inflammasome assembly
Lu, A. Z., & Wu, H. (2014) · FEBS Journal · doi:10.1111/febs.13133 · Cited by 219 · see citing works
Self-citationSchleich, K., Warnken, U., Fricker, N., Öztürk, S., Richter, P., Kammerer, K., Schnölzer, M., Krammer, P. H., & Lavrik, I. N. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.006 · Cited by 198 · see citing works
The Structure of FADD and Its Mode of Interaction with Procaspase-8
Carrington, P. E., Sandu, C., Wei, Y., Hill, J. M., Morisawa, G., Huang, T., Gavathiotis, E., Wei, Y., & Werner, M. H. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.04.018 · Cited by 188 · see citing works
Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism
Lu, A. Z., Li, Y., Schmidt, F. I., Yin, Q., Chen, S., Fu, T., Tong, A., Ploegh, H. L., Mao, Y., & Wu, H. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3199 · Cited by 186 · see citing works
Self-citationQiao, Q., Yang, C., Zheng, C., Fontán, L., David, L., Yu, X., Bracken, C., Rosen, M. L., Melnick, A. M., Egelman, E. H., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.032 · Cited by 176 · see citing works
Self-citationMechanism of procaspase-8 activation by c-FLIP L
Yu, J. W., Jeffrey, P. D., & Shi, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812453106 · Cited by 157 · see citing works
Siegel, R. M., Muppidi, J. R., Sarker, M., Lobito, A. A., Jen, M. V., Martin, D., Straus, S. E., & Lenardo, M. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200406101 · Cited by 146 · see citing works
Self-citationHelical assembly in the death domain (DD) superfamily
Ferrao, R., & Wu, H. (2012) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2012.02.006 · Cited by 142 · see citing works
Self-citationCrystal Structure of MC159 Reveals Molecular Mechanism of DISC Assembly and FLIP Inhibition
Yang, J. K., Wang, L., Zheng, L., Wan, F., Ahmed, M., Lenardo, M. J., & Wu, H. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.023 · Cited by 140 · see citing works
Self-citationReconstruction of Helical Filaments and Tubes
Egelman, E. H. (2010) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(10)82006-3 · Cited by 128 · see citing works
Self-citationCrystal Structure of a vFlip-IKKγ Complex: Insights into Viral Activation of the IKK Signalosome
Bagnéris, C., Ageichik, A. V., Cronin, N., Wallace, B. A., Collins, M. K., Boshoff, C., Waksman, G., & Barrett, T. E. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.029 · Cited by 124 · see citing works
A Novel Flow Cytometric Method To Assess Inflammasome Formation
Sester, D. P., Thygesen, S. J., Sagulenko, V., Vajjhala, P. R., Cridland, J. A., Vitak, N., Chen, K. W., Osborne, G. W., Schroder, K., & Stacey, K. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401110 · Cited by 119 · see citing works
Self-citationOverview: apoptotic signaling pathways in the immune system
Green, D. R. (2003) · Immunological Reviews · doi:10.1034/j.1600-065x.2003.00045.x · Cited by 117 · see citing works
Protein-based therapeutic approaches targeting death receptors
French, L. E., & Tschopp, J. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401185 · Cited by 102 · see citing works
The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments
Vajjhala, P. R., Lu, A. Z., Brown, D. L., Pang, S. W., Sagulenko, V., Sester, D. P., Cridland, S. O., Hill, J. M., Schroder, K., Stow, J. L., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.687731 · Cited by 92 · see citing works
Self-citationCrystal Structure of a Viral FLIP
Li, F.-Y., Jeffrey, P. D., Yu, J. W., & Shi, Y. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m511074200 · Cited by 86 · see citing works
Schleich, K., Buchbinder, J. H., Pietkiewicz, S., Kähne, T., Warnken, U., Öztürk, S., Schnölzer, M., Naumann, M., Krammer, P. H., & Lavrik, I. N. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.137 · Cited by 86 · see citing works
Majkut, J., Sgobba, M., Holohan, C., Crawford, N., Logan, A. E., Kerr, E., Higgins, C. A., Redmond, K. L., Riley, J. S., Stasik, I., et al. (2014) · Nature Communications · doi:10.1038/ncomms4350 · Cited by 81 · see citing works
Esposito, D., Sankar, A., Morgner, N., Robinson, C. V., Rittinger, K., & Driscoll, P. C. (2010) · Structure · doi:10.1016/j.str.2010.08.006 · Cited by 57 · see citing works
The Tandem CARDs of NOD2: Intramolecular Interactions and Recognition of RIP2
Fridh, V., & Rittinger, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034375 · Cited by 46 · see citing works
Structural Study of the RIPoptosome Core Reveals a Helical Assembly for Kinase Recruitment
Jang, T.-H., Zheng, C., Li, J., Richards, C., Hsiao, Y., Walz, T., Wu, H., & Park, H. H. (2014) · Biochemistry · doi:10.1021/bi500585u · Cited by 31 · see citing works
Self-citationTsukumo, S., & Yonehara, S. (1999) · Genes to Cells · doi:10.1046/j.1365-2443.1999.00280.x · Cited by 30 · see citing works
Crystal structure of the death effector domains of caspase-8
Shen, C., Yue, H., Pei, J., Guo, X., Wang, T., & Quan, J. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.05.054 · Cited by 25 · see citing works
Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface
Wu, H., & Hymowitz, S. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00040-1 · Cited by 25 · see citing works
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Newton, K., Strasser, A., Kayagaki, N., & Dixit, V. M. (2024) · Cell · doi:10.1016/j.cell.2023.11.044 · Cited by 1,029 · see citing works
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Samir, P., Malireddi, R. K. S., & Kanneganti, T.-D. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00238 · Cited by 557 · see citing works
Wang, Y., & Kanneganti, T.-D. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.07.038 · Cited by 545 · see citing works
Targeting apoptotic caspases in cancer
Boice, A., & Bouchier‐Hayes, L. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118688 · Cited by 402 · see citing works
The concept of intrinsic versus extrinsic apoptosis
Lossi, L. (2022) · Biochemical Journal · doi:10.1042/bcj20210854 · Cited by 355 · see citing works
Schneider, K. S., Groß, C. J., Dreier, R. F., Saller, B. S., Mishra, R., Gorka, O., Heilig, R., Meunier, É., Dick, M. S., Ćiković, T., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.12.018 · Cited by 293 · see citing works
Programming inflammatory cell death for therapy
Christgen, S. L., Tweedell, R. E., & Kanneganti, T. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108010 · Cited by 290 · see citing works
Caspase-8: The double-edged sword
Mandal, R., Compte, J., Kostova, I., Becker, S., & Strebhardt, K. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188357 · Cited by 252 · see citing works
The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia
Zheng, Z., Deng, W., Bai, Y., Miao, R., Mei, S., Zhang, Z., Pan, Y., Wang, Y., Min, R., Deng, F., et al. (2021) · Science · doi:10.1126/science.abg0269 · Cited by 197 · see citing works
Chen, M., & Ludtke, S. J. (2021) · Nature Methods · doi:10.1038/s41592-021-01220-5 · Cited by 186 · see citing works
Chen, J., Kos, R., Garssen, J., & Redegeld, F. A. (2019) · Cells · doi:10.3390/cells8121486 · Cited by 179 · see citing works
Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury
Kayagaki, N., Stowe, I. B., Alegre, K. O., Deshpande, I., Wu, S., Lin, Z., Kornfeld, O. S., Lee, B. L., Zhang, J., Liu, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06191-5 · Cited by 192 · see citing works
Caspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis
Tummers, B., Mari, L., Guy, C. S., Heckmann, B. L., Rodríguez, D. A., Rühl, S., Moretti, J., Crawford, J. C., Fitzgerald, P., Kanneganti, T., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.010 · Cited by 166 · see citing works
Li, Y., Fu, T., Lu, A. Z., Witt, K. C., Ruan, J., Shen, C., & Wu, H. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810524115 · Cited by 153 · see citing works
Self-citationcFLIP L protects macrophages from LPS-induced pyroptosis via inhibition of complex II formation
Muendlein, H. I., Jetton, D., Connolly, W. M., Eidell, K. P., Magri, Z., Smirnova, I., & Poltorak, A. N. (2020) · Science · doi:10.1126/science.aay3878 · Cited by 137 · see citing works
Crashing the computer: apoptosis vs. necroptosis in neuroinflammation
Heckmann, B. L., Tummers, B., & Green, D. R. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0195-3 · Cited by 132 · see citing works
Hu, X., Li, Z., Lin, R., Shan, J.-Q., Yu, Q., Wang, R., Liao, L., Yan, W., Zhen, W., Shang, L., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.634690 · Cited by 127 · see citing works
Self-citationHeilig, R., Dilucca, M., Boucher, D., Chen, K. W., Hancz, D., Demarco, B., Shkarina, K., & Brož, P. (2020) · Life Science Alliance · doi:10.26508/lsa.202000735 · Cited by 120 · see citing works
Control of Cell Death in Health and Disease
Kayagaki, N., Webster, J. D., & Newton, K. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051022-014433 · Cited by 124 · see citing works
The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways
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David, L., Li, Y., Ma, J., Garner, E. C., Zhang, X., & Wu, H. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1721967115 · Cited by 110 · see citing works
Self-citationThe intra‐ and extracellular functions of ASC specks
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Clabbers, M. T. B., Holmes, S., Muusse, T. W., Vajjhala, P. R., Thygesen, S. J., Malde, A. K., Hunter, D. J. B., Croll, T. I., Flueckiger, L., Nanson, J. D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22590-6 · Cited by 99 · see citing works
Self-citationKucka, K., & Wajant, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.615141 · Cited by 97 · see citing works
Caspase-8 in inflammatory diseases: a potential therapeutic target
Zhang, W., Zhu, C., Liao, Y., Zhou, M., Xu, W., & Zou, Z. (2024) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00646-x · Cited by 97 · see citing works
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Li, Y., Fu, T., & Lu, A. Z. (2018) · Worldwide Protein Data Bank · doi:10.2210/pdb6n1h/pdb · Cited by 89 · see citing works
Self-citationThe role of caspase-8 in inflammatory signalling and pyroptotic cell death
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Sagulenko, V., Vitak, N., Vajjhala, P. R., Vince, J. E., & Stacey, K. J. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.10.028 · Cited by 87 · see citing works
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Nadendla, E. K., Tweedell, R. E., Kasof, G. M., & Kanneganti, T. (2025) · Cell Discovery · doi:10.1038/s41421-025-00791-3 · Cited by 87 · see citing works
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Seyrek, K., Richter, M., & Lavrik, I. N. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0317-6 · Cited by 73 · see citing works
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Fox, J. L., Hughes, M. A., Meng, X., Sarnowska, N. A., Powley, I. R., Jukes‐Jones, R., Dinsdale, D. D., Ragan, T. J., Fairall, L., Schwabe, J. W. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20806-9 · Cited by 70 · see citing works
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Cross talk between intracellular pathogens and cell death
Demarco, B., Chen, K. W., & Brož, P. (2020) · Immunological Reviews · doi:10.1111/imr.12892 · Cited by 60 · see citing works
Vogeler, S., Carboni, S., Li, X., & Joyce, A. (2021) · BMC Genomics · doi:10.1186/s12864-021-07380-0 · Cited by 61 · see citing works
Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
Fianco, G., Contadini, C., Ferri, A., Cirotti, C., Stagni, V., & Barilà, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123798 · Cited by 62 · see citing works
Uzunparmak, B., Gao, M., Lindemann, A., Erikson, K., Wang, L., Lin, E., Frank, S. J., Gleber‐Netto, F. O., Zhao, M., Skinner, H. D., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.139837 · Cited by 61 · see citing works
Regulation of Caspase-8 Activity at the Crossroads of Pro-Inflammation and Anti-Inflammation
Han, J., Park, J., Kang, T., & Lee, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073318 · Cited by 58 · see citing works
Poxviral Strategies to Overcome Host Cell Apoptosis
Suraweera, C. D., Hinds, M. G., & Kvansakul, M. (2020) · Pathogens · doi:10.3390/pathogens10010006 · Cited by 59 · see citing works
Proteomic analysis of necroptotic extracellular vesicles
Shlomovitz, I., Erlich, Z., Arad, G., Edry‐Botzer, L., Zargarian, S., Cohen, H., Manko, T., Ofir‐Birin, Y., Cooks, T., Regev‐Rudzki, N., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04317-z · Cited by 55 · see citing works
Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases
Risso, V., Lafont, É., & Gallo, M. L. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04688-x · Cited by 58 · see citing works
Higher-order assemblies in immune signaling: supramolecular complexes and phase separation
Xia, S., Chen, Z., Shen, C., & Fu, T. (2021) · Protein & Cell · doi:10.1007/s13238-021-00839-6 · Cited by 55 · see citing works
Self-citationDavidovich, P. B., Higgins, C. A., Najda, Z., Longley, D. B., & Martin, S. J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113476 · Cited by 57 · see citing works
Wajant, H. (2019) · Cancers · doi:10.3390/cancers11070954 · Cited by 52 · see citing works
A revised model of TRAIL‐R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis
Humphreys, L. M., Fox, J. P., Higgins, C. A., Majkut, J., Sessler, T., McLaughlin, K. M., McCann, C. K., Roberts, J. Z., Crawford, N., McDade, S. S., et al. (2020) · EMBO Reports · doi:10.15252/embr.201949254 · Cited by 51 · see citing works
Johnston, A. N., Ma, Y., Liu, H., Liu, S., Hanna-Addams, S., Chen, S., Chen, C., & Wang, Z. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1916503117 · Cited by 52 · see citing works
Ivanisenko, N. V., Seyrek, K., Kolchanov, N. A., Иванисенко, В. А., & Lavrik, I. N. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-00331-w · Cited by 51 · see citing works
Functional role of PGAM5 multimeric assemblies and their polymerization into filaments
Ruiz, K., Thaker, T. M., Agnew, C., Miller-Vedam, L. E., Trenker, R., Herrera, C., Ingaramo, M., Toso, D. B., Frost, A. S., & Jura, N. (2019) · Nature Communications · doi:10.1038/s41467-019-08393-w · Cited by 48 · see citing works
TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems
Zeinabad, H. A., & Szegezdi, É. (2022) · Cancers · doi:10.3390/cancers14205125 · Cited by 45 · see citing works
Paving TRAIL’s Path with Ubiquitin
Lafont, É., Hartwig, T., & Walczak, H. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.11.002 · Cited by 45 · see citing works
Death domain fold proteins in immune signaling and transcriptional regulation
Huoh, Y., & Hur, S. (2021) · FEBS Journal · doi:10.1111/febs.15901 · Cited by 43 · see citing works
Smyth, P., Sessler, T., Scott, C. J., & Longley, D. B. (2020) · FEBS Journal · doi:10.1111/febs.15260 · Cited by 43 · see citing works
Dissecting DISC regulation via pharmacological targeting of caspase-8/c-FLIPL heterodimer
Hillert-Richter, L. K., Ivanisenko, N. V., Busse, D., Espe, J., König, C., Peltek, S. E., Kolchanov, N. A., Иванисенко, В. А., & Lavrik, I. N. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0489-0 · Cited by 38 · see citing works
Castelli, G., Pelosi, E., & Testa, U. (2019) · Cancers · doi:10.3390/cancers11020260 · Cited by 38 · see citing works
Shi, M., Zhang, P., Vora, S. M., & Wu, H. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.03.002 · Cited by 38 · see citing works
Self-citationLong and short isoforms of c-FLIP act as control checkpoints of DED filament assembly
Hillert-Richter, L. K., Ivanisenko, N. V., Espe, J., König, C., Иванисенко, В. А., Kähne, T., & Lavrik, I. N. (2019) · Oncogene · doi:10.1038/s41388-019-1100-3 · Cited by 35 · see citing works
Controlling Hair Loss by Regulating Apoptosis in Hair Follicles: A Comprehensive Overview
Wang, W., Wang, H.-L., Long, Y., Li, Z., & Li, J. (2023) · Biomolecules · doi:10.3390/biom14010020 · Cited by 34 · see citing works
Self-citationMahdizadeh, S. J., THOMAS, M. L., & Eriksson, L. A. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c00301 · Cited by 30 · see citing works
Maji, A., Paul, A., Sarkar, A., Nahar, S., Bhowmik, R., Samanta, A., Nahata, P., Ghosh, B., Karmakar, S., & Maity, T. K. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116041 · Cited by 31 · see citing works
Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis
Yang, C., Lien, C.-I., Tseng, Y.-C., Tu, Y.-F., Kulczyk, A., Lu, Y.-C., Wang, Y.-T., Su, T.-W., Hsu, L.-C., Lo, Y.-C., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47990-2 · Cited by 31 · see citing works
Sekar, G., Ojoawo, A. M., & Moldoveanu, T. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220323 · Cited by 31 · see citing works
Stöhr, D., Jeltsch, A., & Rehm, M. (2020) · International review of cytology · doi:10.1016/bs.ircmb.2020.02.002 · Cited by 31 · see citing works
Quantitative single cell analysis uncovers the life/death decision in CD95 network
Buchbinder, J. H., Pischel, D., Sundmacher, K., Flassig, R., & Lavrik, I. N. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006368 · Cited by 28 · see citing works
Ellaway, J. I. J., Anyango, S., Nair, S. S., Zaki, H. A., Nadzirin, N., Powell, H. R., Gutmanas, A., Váradi, M., & Velankar, S. S. (2024) · Structural Dynamics · doi:10.1063/4.0000251 · Cited by 27 · see citing works
Nanson, J. D., Rahaman, M. H., Ve, T., & Kobe, B. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.05.002 · Cited by 26 · see citing works
Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids
Stöhr, D., Schmid, J. O., Beigl, T. B., Mack, A., Maichl, D. S., Cao, K., Budai, B., Fullstone, G., Kontermann, R. E., Mürdter, T. E., et al. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0559-3 · Cited by 25 · see citing works
Kim, S.-J., Lu, H. C., Steelman, A. J., & Li, J. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2117636119 · Cited by 25 · see citing works
Caspase family in autoimmune diseases
Zhang, W., Wu, H., Liao, Y., Zhu, C., & Zou, Z. (2024) · Autoimmunity Reviews · doi:10.1016/j.autrev.2024.103714 · Cited by 26 · see citing works
Self-citationRole of Cell Death in Cellular Processes During Odontogenesis
Abramyan, J., Geetha‐Loganathan, P., Šulcová, M., & Buchtová, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.671475 · Cited by 25 · see citing works
Targeting caspase-8: a new strategy for combating hepatocellular carcinoma
Chen, H., Lin, Y., Chen, J., Luo, X., Kan, Y., He, Y., Zhu, R., Jin, J., Li, D., Wang, Y., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1501659 · Cited by 23 · see citing works
Gasdermin E-mediated programmed cell death: An unpaved path to tumor suppression
Wang, Y., Peng, J., Xie, X., Zhang, Z., Li, M., & Yang, M. W. (2021) · Journal of Cancer · doi:10.7150/jca.48989 · Cited by 23 · see citing works
Alternative approaches to overcome chemoresistance to apoptosis in cancer
Balaji, S., Terrero, D., Tiwari, A. K., Ashby, C. R., & Raman, D. (2021) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.01.005 · Cited by 23 · see citing works
Structural basis for dimerization of the death effector domain of the F122A mutant of Caspase-8
Shen, C., Pei, J., Guo, X., Zhou, L., Li, Q., & Quan, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-35153-5 · Cited by 21 · see citing works
Structural and mechanistic elucidation of inflammasome signaling by cryo-EM
Shen, C., Sharif, H., Xia, S., & Wu, H. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.03.033 · Cited by 21 · see citing works
Self-citationFn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling
Siegmund, D., Zaitseva, O., & Wajant, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1267837 · Cited by 20 · see citing works
Huo, Y., Ding, W., Liu, Y., Li, Z.-T., Dai, K.-Y., Liu, C., Ji, H.-Y., & Liu, A. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131812 · Cited by 20 · see citing works
Self-citationKobe, B., Nanson, J. D., Hoad, M., Blumenthal, A., Gambin, Y., Sierecki, E., Stacey, K. J., Ve, T., & Halfmann, R. (2025) · Biochemical Journal · doi:10.1042/bcj20220094 · Cited by 23 · see citing works
Self-citationCell death classification: A new insight based on molecular mechanisms
Dehghan, S., Kheshtchin, N., Hassannezhad, S., & Soleimani, M. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113860 · Cited by 18 · see citing works
Park, H. H. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0200-x · Cited by 18 · see citing works
Mechanisms of Procaspase-8 Activation in the Extrinsic Programmed Cell Death Pathway
Ivanisenko, N. V., & Lavrik, I. N. (2019) · Molecular Biology · doi:10.1134/s0026893319050091 · Cited by 18 · see citing works
Soni, I. V., & Hardy, J. A. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00459 · Cited by 17 · see citing works
Lafont, É. (2020) · Cancers · doi:10.3390/cancers12051113 · Cited by 18 · see citing works
Caspase cleavage of RIPK3 after Asp333 is dispensable for mouse embryogenesis
Newton, K., Wickliffe, K. E., Maltzman, A., Dugger, D. L., Webster, J. D., Guo, H., & Dixit, V. M. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-023-01255-5 · Cited by 16 · see citing works
Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death
Wyatt, J., Müller, M. M., & Tavassoli, M. (2019) · Cancers · doi:10.3390/cancers11121975 · Cited by 16 · see citing works
The Role of Post-Translational Modifications in Necroptosis
Xiao, H., Han, Z., Xu, M., Gao, X., Qiu, S., Ren, N., Yi, Y., & Zhou, C. (2025) · Biomolecules · doi:10.3390/biom15040549 · Cited by 15 · see citing works
Assembly and activation of the death-inducing signaling complex
Fosuah, E., Shen, Z., Xie, J., Chen, W., Lin, Q., & Fu, T. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2504819122 · Cited by 15 · see citing works
Self-citationHellwig, C. T., Delgado, M. E., Skoko, J., Dyck, L., Hanna, C., Wentges, A., Langlais, C., Hagenlocher, C., Mack, A., Dinsdale, D. D., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00843-7 · Cited by 15 · see citing works
Ehrlichia Notch signaling induction promotes XIAP stability and inhibits apoptosis
Patterson, L. L., Byerly, C. D., Solomon, R. N., Pittner, N. A., Bui, D., Patel, J. G., & McBride, J. W. (2023) · Infection and Immunity · doi:10.1128/iai.00002-23 · Cited by 15 · see citing works
The dual role of the CD95 and CD95L signaling pathway in glioblastoma
Zhang, Y., Jin, T., Dou, Z., Wei, B., Zhang, B., & Sun, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1029737 · Cited by 14 · see citing works
Modulation of extrinsic apoptotic pathway by intracellular glycosylation
Seyrek, K., Ivanisenko, N. V., König, C., & Lavrik, I. N. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.01.003 · Cited by 14 · see citing works
Ivanisenko, N. V., Buchbinder, J. H., Espe, J., Richter, M., Bollmann, M., Hillert-Richter, L. K., Иванисенко, В. А., & Lavrik, I. N. (2019) · BMC Genomics · doi:10.1186/s12864-019-5539-y · Cited by 14 · see citing works
Mollinedo, F., & Gajate, C. (2022) · Biochemical Society Transactions · doi:10.1042/bst20211115 · Cited by 13 · see citing works
- Authors
- Fu, T.-M., Li, Y., Lu, A., Li, Z., Vajjhala, P. R., Cruz, A. C., Srivastava, D. B., DiMaio, F., Penczek, P. A., Siegel, R. M., Stacey, K. J., Egelman, E. H., & Wu, H.
- Affiliations
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- The University of Queensland (AU)
- National Institutes of Health (US)
- University of Washington (US)
- Texas Medical Center (US)
- University of Virginia (US)
- Corresponding author
- Wu, Hao
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 64
- Issue
- 2
- Pages
- 236-250
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5089849
- OpenAlex
- W2531084658
- Cited by
- 196
- References
- 48
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 24 · 2023: 9 · 2022: 16 · 2021: 35 · 2020: 25 · 2019: 24 · 2018: 13 · 2017: 10 · 2016: 1
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Health and Medical Research Council
- National Medical Research Council
- National Institute of General Medical Sciences (R01GM060635)
- National Institute of Allergy and Infectious Diseases (R37AI050872, R01AI045937, R01AI124491)
- National Institute of Biomedical Imaging and Bioengineering (R01EB001567)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP1HD087988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- caspase-8, death-inducing signaling complex, FADD, c-FLIP, ASC, inflammasome, death receptor signaling, caspase activation, protein filament assembly, protein-protein interfaces, Fas-mediated apoptosis, caspase inhibition
- MeSH terms
- Death Effector Domain, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Amino Acid Sequence, Binding Sites, Cytoskeletal Proteins, Humans, Plasmids, Protein Binding, Recombinant Fusion Proteins, Transfection, Viral Proteins, Gene Expression, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, fas Receptor, Jurkat Cells, Cryoelectron Microscopy, Caspase 8, Fas-Associated Death Domain Protein, Death Domain Receptor Signaling Adaptor Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, CARD Signaling Adaptor Proteins, Protein Interaction Domains and Motifs
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