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Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex
Open accessAbstract
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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“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]
In the citing paper
“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]
Citations
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 4,709
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
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
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
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
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
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
Self-citationA 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 986
The 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
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 878
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 837
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
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
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 423
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
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
The 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 283
Self-citationPark, 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
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
(2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.x0001-0 · Cited by 257
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 248
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
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
Self-citationStructural mechanisms of inflammasome assembly
Lu, A. Z., & Wu, H. (2014) · FEBS Journal · doi:10.1111/febs.13133 · Cited by 231
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 227
Schleich, 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
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 196
Self-citationThe 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
Qiao, 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 173
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
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
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 145
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 141
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 127
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
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
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
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
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 94
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
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
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
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 59
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
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
Self-citationTsukumo, S., & Yonehara, S. (1999) · Genes to Cells · doi:10.1046/j.1365-2443.1999.00280.x · Cited by 30
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
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
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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