Caspase-8 Acts in a Non-enzymatic Role as a Scaffold for Assembly of a Pro-inflammatory “FADDosome” Complex upon TRAIL Stimulation
Open accessAbstract
TRAIL is a potent inducer of apoptosis and has been studied almost exclusively in this context. However, TRAIL can also induce NFκB-dependent expression of multiple pro-inflammatory cytokines and chemokines. Surprisingly, whereas inhibition of caspase activity blocked TRAIL-induced apoptosis, but not cytokine production, knock down or deletion of caspase-8 suppressed both outcomes, suggesting that caspase-8 participates in TRAIL-induced inflammatory signaling in a scaffold role. Consistent with this, introduction of a catalytically inactive caspase-8 mutant into CASP-8 null cells restored TRAIL-induced cytokine production, but not cell death. Furthermore, affinity precipitation of the native TRAIL receptor complex revealed that pro-caspase-8 was required for recruitment of RIPK1, via FADD, to promote NFκB activation and pro-inflammatory cytokine production downstream. Thus, caspase-8 can serve in two distinct roles in response to TRAIL receptor engagement, as a scaffold for assembly of a Caspase-8-FADD-RIPK1 "FADDosome" complex, leading to NFκB-dependent inflammation, or as a protease that promotes apoptosis.
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Ability of some death receptors including TNFR1 to promote NF-κB activation over CASP8 activation depends on degree of receptor oligomerization, scaffolding functions of CASP8, and assembly of TNFR1-like complexes containing RIPK1 and LUBAC.
“The ability of some death receptors including TNFR1 to promote NF-κB activation over CASP8 activation appears to depend on the degree of receptor oligomerization (i.e., trimerization vs. higher-order multimerization) [343], the scaffolding (i.e., non-enzymatic) functions of CASP8, and the consequent assembly of TNFR1-like complexes containing RIPK1 and LUBAC [272, 286, 344].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [344]
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Cites
Identification and characterization of a new member of the TNF family that induces apoptosis
Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., et al. (1995) · Immunity · doi:10.1016/1074-7613(95)90057-8 · Cited by 2,900 · see citing works
TNF-α Induces Two Distinct Caspase-8 Activation Pathways
Wang, L., Du, F., & Wang, X. (2008) · Cell · doi:10.1016/j.cell.2008.03.036 · Cited by 1,352 · see citing works
Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R. (2011) · Nature · doi:10.1038/nature09852 · Cited by 1,278 · cited 2× · see citing works
“…Molecular Cell 65, 715–729, February 16, 2017 ‘‘Ripoptosome’’ (that promotes apoptosis), and the RIPK1/ RIPK3 necrosome (that promotes necroptosis), most likely functioning to set a threshold on caspase-8 activity in these pathways (Sprick et al., 2000; Tenev et al., 2011; Oberst et al., 2011).”
BackgroundIAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis
Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.030 · Cited by 1,218 · see citing works
IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis
Vince, J. E., Wong, W. W.-L., Khan, N. R., Feltham, R., Chau, D., Ahmed, A. U., Benetatos, C. A., Chunduru, S. K., Condon, S. M., McKinlay, M. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.037 · Cited by 1,061 · see citing works
Apo2L/TRAIL-Dependent Recruitment of Endogenous FADD and Caspase-8 to Death Receptors 4 and 5
Kischkel, F. C., Lawrence, D. A., Chuntharapai, A., Schow, P., Kim, K. J., & Ashkenazi, A. (2000) · Immunity · doi:10.1016/s1074-7613(00)80212-5 · Cited by 975 · see citing works
Cleavage of the death domain kinase RIP by Caspase-8 prompts TNF-induced apoptosisPreprint
Lin, Y., Devin, A., Rodriguez, Y., & Liu, Z.-G. (1999) · Genes & Development · doi:10.1101/gad.13.19.2514 · Cited by 835 · 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
NF-κB Signals Induce the Expression of c-FLIP
Micheau, O., Lens, S. M. A., Gaide, O., Alevizopoulos, K., & Tschopp, J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.16.5299-5305.2001 · Cited by 809 · see citing works
Sprick, M. R., Weigand, M. A., Rieser, E., Rauch, C. T., Juo, P., Blenis, J., Krammer, P. H., & Walczak, H. (2000) · Immunity · doi:10.1016/s1074-7613(00)80211-3 · Cited by 799 · see citing works
Apoptosis and cancer: mutations within caspase genes
Ghavami, S., Hashemi, M. M., Ande, S. R., Yeganeh, B., Xiao, W., Eshraghi, M., Bus, C., Kadkhoda, K., Wiecheć, E., Halayko, A. J., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2009.066944 · Cited by 712 · see citing works
TRAIL Receptors 1 (DR4) and 2 (DR5) Signal FADD-Dependent Apoptosis and Activate NF-κB
Schneider, P., Thome, M., Burns, K., Bodmer, J.-L., Hofmann, K., Kataoka, T., Holler, N., & Tschopp, J. (1997) · Immunity · doi:10.1016/s1074-7613(00)80401-x · Cited by 697 · see citing works
Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., Sun, L., Chen, Z. J., Marynen, P., & Beyaert, R. (2008) · Nature Immunology · doi:10.1038/ni1561 · Cited by 437 · see citing works
Regulation of NF-κB-Dependent Lymphocyte Activation and Development by Paracaspase
Ruefli-Brasse, A. A., French, D. M., & Dixit, V. M. (2003) · Science · doi:10.1126/science.1090769 · Cited by 381 · see citing works
Sprick, M. R., Rieser, E., Stahl, H. F., Große-Wilde, A., Weigand, M. A., & Walczak, H. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf441 · Cited by 364 · 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
Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines
Henry, C. M., Sullivan, G. P., Clancy, D. M., Afonina, I. S., Kulms, D., & Martin, S. J. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.072 · Cited by 330 · see citing works
Self-citationVarfolomeev, E. E., Maecker, H. L., Sharp, D. A., Lawrence, D. A., Renz, M. E., Vucic, D., & Ashkenazi, A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509560200 · Cited by 278 · see citing works
Ermolaeva, M., Michallet, M., Papadopoulou, N., Utermöhlen, O., Kranidioti, K., Kollias, G. A., Tschopp, J., & Pasparakis, M. (2008) · Nature Immunology · doi:10.1038/ni.1638 · Cited by 277 · see citing works
Jeltsch, K. M., Hu, D., Brenner, S., Zöller, J., Heinz, G. A., Nagel, D., Vogel, K. U., Rehage, N., Warth, S. C., Edelmann, S. L., et al. (2014) · Nature Immunology · doi:10.1038/ni.3008 · Cited by 274 · see citing works
Ehrhardt, H., Fulda, S., Schmid, I., Hiscott, J. B., Debatin, K., & Jeremias, I. (2003) · Oncogene · doi:10.1038/sj.onc.1206520 · Cited by 272 · see citing works
Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
Kang, S., Fernandes‐Alnemri, T., Rogers, C., Mayes, L., Wang, Y., Dillon, C. P., Roback, L., Kaiser, W. J., Oberst, A., Sagara, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms8515 · Cited by 255 · see citing works
Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4
Todaro, M., Lombardo, Y., Francipane, M., Alea, M. P., Cammareri, P., Iovino, F., Stefano, A. D. D., Bernardo, C. D., Agrusa, A., Condorelli, G., et al. (2008) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402305 · Cited by 242 · see citing works
Expression, purification and use of recombinant annexin V for the detection of apoptotic cells
Logue, S. E., Elgendy, M., & Martin, S. J. (2009) · Nature Protocols · doi:10.1038/nprot.2009.143 · Cited by 242 · see citing works
Self-citationActivation of the NF-κB pathway by Caspase 8 and its homologs
Chaudhary, P. M., Eby, M. T., Jasmin, A., Kumar, A., Liu, L., & Hood, L. (2000) · Oncogene · doi:10.1038/sj.onc.1203812 · Cited by 241 · see citing works
Diverse Activators of the NLRP3 Inflammasome Promote IL-1β Secretion by Triggering Necrosis
Cullen, S. P., Kearney, C. J., Clancy, D. M., & Martin, S. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.05.003 · Cited by 234 · see citing works
Self-citationFas/CD95-Induced Chemokines Can Serve as “Find-Me” Signals for Apoptotic Cells
Cullen, S. P., Henry, C. M., Kearney, C. J., Logue, S. E., Feoktistova, M., Tynan, G. A., Lavelle, E. C., Leverkus, M., & Martin, S. J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.025 · Cited by 222 · see citing works
Self-citationvon Karstedt, S., Conti, A., Nobis, M., Montinaro, A., Hartwig, T., Lemke, J., Legler, K., Annewanter, F., Campbell, A. D., Taraborrelli, L., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.02.014 · Cited by 196 · see citing works
Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling
Peltzer, N., Darding, M., & Walczak, H. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.01.006 · Cited by 184 · see citing works
Morel, J., Audo, R., Hahne, M., & Combe, B. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414469200 · Cited by 171 · see citing works
Trail induces cell migration and invasion in apoptosis-resistant cholangiocarcinoma cells
Ishimura, N., Isomoto, H., Bronk, S. F., & Gores, G. J. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00242.2005 · Cited by 155 · see citing works
Sharp, D. A., Lawrence, D. A., & Ashkenazi, A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413962200 · Cited by 152 · see citing works
Gewies, A., Gorka, O., Bergmann, H., Pechloff, K., Petermann, F., Jeltsch, K. M., Rudelius, M., Kriegsmann, M., Weichert, W., Horsch, M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.044 · Cited by 151 · see citing works
Klein, T., Fung, S., Renner, F., Blank, M. A., Dufour, A., Kang, S., Bolger-Munro, M., Scurll, J., Priatel, J. J., Schweigler, P., et al. (2015) · Nature Communications · doi:10.1038/ncomms9777 · Cited by 151 · see citing works
Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity
Jaworski, M., Marsland, B. J., Gehrig, J., Held, W., Favre, S., Luther, S. A., Perroud, M., Golshayan, D., Gaide, O., & Thome, M. (2014) · The EMBO Journal · doi:10.15252/embj.201488987 · Cited by 148 · see citing works
TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells
Secchiero, P., Zerbinati, C., Rimondi, E., Corallini, F., Milani, D., Grill, V., Forti, G., Capitani, S., & Zauli, G. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4197-6 · Cited by 139 · see citing works
Distinct Signaling Pathways in TRAIL- versus Tumor Necrosis Factor-Induced Apoptosis
Jin, Z., & El‐Deiry, W. S. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00257-06 · Cited by 137 · see citing works
Koschny, R., Ganten, T. M., Sykora, J., Haas, T. L., Sprick, M. R., Kolb, A., Stremmel, W., & Walczak, H. (2007) · Hepatology · doi:10.1002/hep.21555 · Cited by 115 · see citing works
Soung, Y. H., Lee, J. W., Kim, S. Y., Sung, Y. J., Park, W. S., Nam, S. W., Kim, S. H., Lee, J. Y., Yoo, N. J., & Lee, S. H. (2004) · Oncogene · doi:10.1038/sj.onc.1208244 · Cited by 111 · see citing works
Chou, A., Tsai, H.-F., Lin, L.-L., Hsieh, S.-L., Hsu, P., & Hsu, P. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.3.1347 · Cited by 102 · see citing works
Kavurma, M. M., Schoppet, M., Bobryshev, Y. V., Khachigian, L. M., & Bennett, M. R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706927200 · Cited by 99 · see citing works
Kavuri, S. M., Geserick, P., Berg, D., Dimitrova, D. P., Feoktistova, M., Siegmund, D., Gollnick, H., Neumann, M., Wajant, H., & Leverkus, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.148585 · Cited by 92 · see citing works
Afonina, I. S., Elton, L., Carpentier, I., & Beyaert, R. (2015) · FEBS Journal · doi:10.1111/febs.13325 · Cited by 82 · see citing works
Caspase‐8 and caspase‐10 activate NF‐κB through RIP, NIK and IKKα kinases
Shikama, Y., Yamada, M., & Miyashita, T. (2003) · European Journal of Immunology · doi:10.1002/eji.200324013 · Cited by 62 · see citing works
A synthetic lethal screen identifies FAT1 as an antagonist of caspase‐8 in extrinsic apoptosis
Kranz, D., & Boutros, M. (2014) · The EMBO Journal · doi:10.1002/embj.201385686 · Cited by 46 · see citing works
Cancer‐associated missense mutations of caspase‐8 activate nuclear factor‐κB signaling
Ando, M., Kawazu, M., Ueno, T., et al. (2013) · Cancer Science · doi:10.1111/cas.12191 · Cited by 44 · see citing works
Berg, D., Stühmer, T., Siegmund, D., et al. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07388.x · Cited by 32 · see citing works
Bullenkamp, J., Raulf, N., Ayaz, B., Walczak, H., Kulms, D., Odell, E. W., Thavaraj, S., & Tavassoli, M. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.455 · Cited by 30 · see citing works
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Self-citationExploring the TRAILs less travelled: TRAIL in cancer biology and therapy
von Karstedt, S., Montinaro, A., & Walczak, H. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.28 · Cited by 556 · see citing works
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- Authors
- Henry, C. M., & Martin, S. J.
- Affiliations
- Trinity College Dublin (IE)
- ORCID
- Henry, Conor M.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 65
- Issue
- 4
- Pages
- 715-729.e5
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2588177032
- Cited by
- 267
- References
- 48
- Citations by year
- 2026: 12 · 2025: 31 · 2024: 32 · 2023: 27 · 2022: 32 · 2021: 33 · 2020: 34 · 2019: 30 · 2018: 17 · 2017: 18
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Investigator award
- Science Foundation Ireland (14/IA/2622)
- Worldwide Cancer Research (14-0323)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- caspase-8, TRAIL, FADD, RIPK1, NF-κB activation, apoptosis, inflammatory signaling
- MeSH terms
- Animals, Antineoplastic Agents, Chemotaxis, Dose-Response Relationship, Drug, Female, HeLa Cells, Humans, Neoplasms, Phagocytes, Time Factors, Transfection, Signal Transduction, Cytokines, NF-kappa B, Apoptosis, Inflammation Mediators, HT29 Cells, RNA Interference, HCT116 Cells, Multiprotein Complexes, Mice, Caspase 8, Fas-Associated Death Domain Protein, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, Receptor-Interacting Protein Serine-Threonine Kinases, HEK293 Cells
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