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Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Open accessAbstract
Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.
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“In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [479]
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Two CD95 (APO‐1/Fas) signaling pathways
Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K. J., Debatin, K., Krammer, P. H., & Peter, M. E. (1998) · The EMBO Journal · doi:10.1093/emboj/17.6.1675 · Cited by 3,000
Cho, 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 · cited 1×
“Necrosis induced by TNF in the presence of caspase inhibitors is dependent on the kinase activity of Receptor-Interacting Protein Kinase-1 (RIPK1)4,8 and RIPK39–11, although the mechanisms remain obscure.”
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
Identification of RIP1 kinase as a specific cellular target of necrostatins
Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.83 · Cited by 2,059 · cited 1×
“Necrosis induced by TNF in the presence of caspase inhibitors is dependent on the kinase activity of Receptor-Interacting Protein Kinase-1 (RIPK1)4,8 and RIPK39–11, although the mechanisms remain obscure.”
Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.-L., Schneider, P., Seed, B., & Tschopp, J. (2000) · Nature Immunology · doi:10.1038/82732 · Cited by 1,987 · cited 12×
“Cleaved caspase-8 was observed in whole lysates from these cells upon FLIP knockdown and TNF treatment, indicating that active caspase-8 was present in these cells, but was unable to prevent formation of the RIPK1-RIPK3 complex in the absence of FLIP (fig.”
InfluentialRIP3, 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
Lethal effect of the anti-Fas antibody in mice
Ogasawara, J., Watanabe-Fukunaga, R., Adachi, M., Matsuzawa, A., Kasugai, T., Kitamura, Y., Itoh, N., Suda, T., & Nagata, S. (1993) · Nature · doi:10.1038/364806a0 · Cited by 1,881
Varfolomeev, E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J., Mett, I., Rebrikov, D., Brodianski, V. M., Kemper, O., Kollet, O., et al. (1998) · Immunity · doi:10.1016/s1074-7613(00)80609-3 · Cited by 1,332
Vercammen, D., Beyaert, R., Denecker, G., Goossens, V., Loo, G., Declercq, W., Grooten, J., Fiers, W., & Vandenabeele, P. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.9.1477 · Cited by 925
FADD: Essential for Embryo Development and Signaling from Some, But Not All, Inducers of Apoptosis
Yeh, W., de la Pompa, J. L., McCurrach, M. E., Shu, H., Elia, A., Shahinian, A., Ng, M. S. W., Wakeham, A. C., Khoo, W., Mitchell, K., et al. (1998) · Science · doi:10.1126/science.279.5358.1954 · Cited by 890
Research works printed but not linked: 4
- Geserick, P. et al. Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J. Cell Biol. 187, 1037–1054 (2009) · DOI
- Oberst, A. et al. Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation. J. Biol. Chem. 285, 16632–16642 (2010) · DOI · Paper page
- Salmena, L. et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 17, 883–895 (2003) · DOI
- Newton, K., Sun, X. & Dixit, V. M. Kinase RIP3 is dispensable for normal NF-κBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 24, 1464–1469 (2004) · DOI
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Tseng, W.-Y., Huang, Y.-S., Lin, H., Luo, S., McCann, F. E., McNamee, K., Clanchy, F. I. L., & Williams, R. O. (2016) · Cytokine · doi:10.1016/j.cyto.2016.08.027 · Cited by 71
Xiao, G., Zhuang, W., Wang, T., Lian, G., Luo, L., Ye, C., Wang, H., & Xie, L. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15745 · Cited by 65
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Fayaz, S. M., Kumar, V. S. S., & Rajanikant, G. K. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113126660189 · Cited by 65
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Giampietri, C., Starace, D., Petrungaro, S., Filippini, A., & Ziparo, E. (2014) · International Journal of Cell Biology · doi:10.1155/2014/490275 · Cited by 63
“Although the molecular complex driving necroptosis during development is not completely clear, results obtained in vitro confirmed that a caspase-8/Flip heterodimer can inhibit RIP signalling to necroptosis [36].”
BackgroundRIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells
Harris, K. G., Morosky, S. A., Drummond, C., Patel, M., Kim, C., Stolz, D. B., Bergelson, J. M., Cherry, S. R., & Coyne, C. B. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.07.007 · Cited by 64
“Although this loss of viability was attributed to the role of RIP3 in necroptotic cell death, in light of our data it is possible that inhibition of caspase-8, a known negative regulator of RIP3 (Oberst et al., 2011), may cause an increase in RIP3-dependent autophagic flux, resulting in autophagic cell death.”
BackgroundThe Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
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Tan, Y., Sementino, E., Cheung, M., Peri, S., Menges, C. W., Kukuyan, A.-M., Zhang, T., Khazak, V., Fox, L. A., Ross, E. A., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3683 · Cited by 63
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Xiao, S.-Q., Miao, C., Wang, L., Cao, J., Fang, L., Zhou, X., He, X.-J., & Hu, Y. (2023) · International Orthopaedics · doi:10.1007/s00264-023-05847-1 · Cited by 68
Suda, J., Dara, L., Yang, L., Aghajan, M., Song, Y., Kaplowitz, N., & Liu, Z. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600690 · Cited by 63
“The levels of RIPK3 expression were demonstrated to correlate with the sensitivity of cells to necroptosis (2, 29, 33, 43, 44).”
BackgroundThe Molecular Links between Cell Death and Inflammasome
Lee, K. H., & Kang, T. (2019) · Cells · doi:10.3390/cells8091057 · Cited by 65
Luo, Y., Benjanuwattra, J., Chattipakorn, S. C., & Chattipakorn, N. (2020) · Acta Physiologica · doi:10.1111/apha.13541 · Cited by 65
Dying to Replicate: The Orchestration of the Viral Life Cycle, Cell Death Pathways, and Immunity
Yatim, N., & Albert, M. L. (2011) · Immunity · doi:10.1016/j.immuni.2011.10.010 · Cited by 65
Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation
Speir, M., Nowell, C. J., Chen, A. A., O’Donnell, J. A., Shamie, I., Lakin, P. R., D’Cruz, A. A., Braun, R. O., Babon, J. J., Lewis, R. S., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0550-7 · Cited by 61
Self-citationTypes of Cell Death from a Molecular Perspective
Hajibabaie, F., Abedpoor, N., & Mohamadynejad, P. (2023) · Biology · doi:10.3390/biology12111426 · Cited by 69
“The activation of caspase-8 by FADD after the activation of death receptors initiates apoptosis, while the lack or pharmacological inhibition of caspase-8 leads to necroptosis [92,100].”
BackgroundThe adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL
Grunert, M., Gottschalk, K., Kapahnke, J., Gündisch, S., Kieser, A., & Jeremias, I. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.154 · Cited by 63
Neuromelanin activates proinflammatory microglia through a caspase-8-dependent mechanism
Viceconte, N., Burguillos, M. Á., Herrera, A. J., de Pablos, R. M., Joseph, B., & Venero, J. L. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0228-x · Cited by 60
“However, recent reports have demonstrated an increased number of non-apoptotic roles for these caspases [3-6].”
Zhang, B., Liu, S.-Q., Li, C., Lykken, E. A., Jiang, S., Wong, E., Gong, Z., Tao, Z., Zhu, B., Wan, Y., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.007 · Cited by 62
“These findings phenocopy the T cell necrosis induced by Casp8, Fadd, Cflar, or Tnfaip3 deletion (Kaiser et al., 2011; Oberst et al., 2011; Onizawa et al., 2015; Zhang et al., 2011).”
BackgroundMoriwaki, K., Balaji, S., Bertin, J., Gough, P. J., & Chan, F. K.-M. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.015 · Cited by 60
“This defect was completely rescued by inactivation of RIPK3 (Kaiser et al., 2011; Oberst et al., 2011).”
InfluentialXiao, R., Allen, C. T., Tran, L. B., Patel, P., Park, S. J., Chen, Z., Waes, C. V., & Schmitt, N. C. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1471440 · Cited by 62
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
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Han, J., Park, J., Kang, T., & Lee, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073318 · Cited by 62
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Tischner, D., Manzl, C., Soratroi, C., Villunger, A., & Krumschnabel, G. (2012) · APOPTOSIS · doi:10.1007/s10495-012-0756-8 · Cited by 59
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Rohde, K., Kleinesudeik, L., Roesler, S., Löwe, O., Heidler, J., Schröder, K., Wittig, I., Dröse, S., & Fulda, S. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.102 · Cited by 60
Targeting apoptosis pathways in infections
Naderer, T., & Fulcher, M. C. (2018) · Journal of Leukocyte Biology · doi:10.1189/jlb.4mr0717-286r · Cited by 62
DeLaney, A. A., Berry, C. T., Christian, D. A., Hart, A. P., Bjånes, E., Wynosky-Dolfi, M. A., Li, X., Tummers, B., Udalova, I. A., Chen, Y. H., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820529116 · Cited by 58
“Distinct IκB proteins preferentially regulate specific NF-κB family members (43).”
BackgroundMethodInfluentialYashin, D. V., Ivanova, O. K., Soshnikova, N. V., Sheludchenkov, A. A., Romanova, E. A., Dukhanina, E. A., Tonevitsky, A., Gnuchev, N. V., Gabibov, A. G., Georgiev, G. P., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.639732 · Cited by 59
Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence
Missiakas, D. M., & Winstel, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.621733 · Cited by 61
Quarato, G., Llambi, F., Guy, C. S., Min, J., Actis, M., Sun, H., Narina, S., Pruett‐Miller, S. M., Peng, J., Ranković, Z., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01025-9 · Cited by 72
Self-citationRevisiting Regulated Cell Death Responses in Viral Infections
Balaya, R. D. A., Prasad, T. S. K., & Kandasamy, R. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137023 · Cited by 60
From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors
Gardner, C. R., Davies, K. A., Zhang, Y., Brzozowski, M., Czabotar, P. E., Murphy, J. M., & Lessène, G. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01621 · Cited by 60
The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation
Imai, T., Lin, J., Kaya, G. G., Ju, E., Kondylis, V., Kelepouras, K., Liccardi, G., KIM, C. S., & Pasparakis, M. (2024) · Immunity · doi:10.1016/j.immuni.2024.04.016 · Cited by 58
Koncz, G., & Hueber, A. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00207 · Cited by 62
“These mice contain B220+ T cells and show splenomegaly and lymphadenopathy (Oberst et al., 2011) due to abnormally high level of T cells.”
BackgroundMolecular Cell Biology of Apoptosis and Necroptosis in Cancer
Dillon, C. P., & Green, D. R. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-39406-0_1 · Cited by 62
Self-citationVasilikos, L., Spilgies, L. M., Knop, J., & Wong, W. W.-L. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.118 · Cited by 61
Sakamaki, K., Imai, K., Tomii, K., & Miller, D. J. (2015) · BioEssays · doi:10.1002/bies.201500010 · Cited by 58
DED or alive: assembly and regulation of the death effector domain complexes
Riley, J. S., Malik, A., Holohan, C., & Longley, D. B. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.213 · Cited by 60
“Thus, formation of the caspase8/FLIPL heterodimer in Complex IIa blocks both apoptosis by preventing procaspase-8 homodimerisation and necroptosis by blocking RIPK1/RIPK3-mediated necroptosis.(85) As is the case for other DED protein-containing complexes, caspase-8/”
BackgroundControlled detonation: evolution of necroptosis in pathogen defense
Brault, M., & Oberst, A. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.117 · Cited by 57
Self-citationTong, Y., Zhang, G., Yang, L., Xu, J., Yuan, J., Zhang, B., Hu, T., & Song, G. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13647 · Cited by 58
“(RIPK1) and recruitment of mixed lineage kinase domain-like protein (MLKL).(33,34) Owing to necroptosis depend on RIP3, we used HT-29 cells as positive control and Hela cells as negative control, detecting the level of RIP1 and RIP3 in MCF-7 and SK-BR3, and found that the level of RIP1 was similar, while SK-BR3 cells…”
MethodMalireddi, R. K. S., Sharma, B. R., Bynigeri, R. R., Wang, Y., Lu, J., & Kanneganti, T. (2023) · Viruses · doi:10.3390/v15112141 · Cited by 62
STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD
Kelepouras, K., Saggau, J., Bonasera, D., Kiefer, C., Locci, F., Rakhsh-Khorshid, H., Grauvogel, L., Varanda, A. B., Peifer, M., Loricchio, E., et al. (2025) · Nature · doi:10.1038/s41586-025-09536-4 · Cited by 64
USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability
Jeong, M., Lee, E.-W., Seong, D., Seo, J., Kim, J.-H., Grootjans, S., Kim, S.-Y., Vandenabeele, P., & Song, J. (2016) · Oncogene · doi:10.1038/onc.2016.215 · Cited by 58
Relevance of necroptosis in cancer
Lalaoui, N., & Brumatti, G. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.120 · Cited by 56
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
Death receptor signalling in central nervous system inflammation and demyelination
Guire, C. M., Beyaert, R., & Loo, G. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.09.002 · Cited by 59
Caspase-8 function, and phosphorylation, in cell migration
Keller, N., Ozmadenci, D., Ichim, G., & Stupack, D. G. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.01.009 · Cited by 60
Someda, M., Kuroki, S., Miyachi, H., Tachibana, M., & Yonehara, S. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0434-2 · Cited by 56
Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis
Karlowitz, R., & van Wijk, S. J. L. (2021) · FEBS Journal · doi:10.1111/febs.16255 · Cited by 59
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Wang, S., Liu, Y., Zhang, L., & Sun, Z. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2021.0504 · Cited by 58
Gasdermin D-deficient mice are hypersensitive to acute kidney injury
Tonnus, W., Maremonti, F., Belavgeni, A., Latk, M., Kusunoki, Y., Brucker, A. M., von Mäßenhausen, A., Meyer, C., Locke, S., Gembardt, F., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05230-9 · Cited by 56
“Apoptosis, a caspase-regulated nonimmunogenic cell death that is not associated with the rupture of the plasma membrane [6], is tightly interconnected to two types of regulated necrotic cell death referred to as necroptosis [7, 8] and pyroptosis [9–14].”
BackgroundInnate immune sensor NLRP3 drives PANoptosome formation and PANoptosis
Sharma, B. R., Choudhury, S. M., Abdelaal, H. M., Wang, Y., & Kanneganti, T. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkaf042 · Cited by 58
Caspase-8 Acts as a Molecular Rheostat To Limit RIPK1- and MyD88-Mediated Dendritic Cell Activation
Cuda, C. M., Misharin, A. V., Gierut, A. K., Saber, R., Haines, G. K., Hutcheson, J., Hedrick, S. Μ., Mohan, C., Budinger, G. R. S., Stehlik, C., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400122 · Cited by 53
“The vast majority of studies on the Fas-signaling pathway in the immune system and its role in apoptosis and necroptosis have focused on lymphocytes.”
InfluentialTargeting c-FLICE-like inhibitory protein (CFLAR) in cancer
Fulda, S. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.736499 · Cited by 56
“This has been attributed to the binding of c-FLIPL to adaptor proteins of the NF-kB cascade, including TNFR-associated factors 1 (TRAF1) and 2 (TRAF2), as well as RIP1 [20-22].”
BackgroundInfluentialPost-translational modifications as key regulators of TNF-induced necroptosis
Liu, X., Shi, F., Li, Y., Yu, X., Peng, S., Li, W., Luo, X., & Cao, Y. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.197 · Cited by 56
Tanzer, M. C., Khan, N. R., Rickard, J. A., Etemadi, N., Lalaoui, N., Spall, S. K., Hildebrand, J. M., Segal, D., Miasari, M., Chau, D., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2016.147 · Cited by 53
“Therefore, blocking caspase-8 not only prevents apoptosis but also unleashes the brake on RIPK1, allowing necroptosis to occur.(19,52,53) cIAPs also inhibit activation of noncanonical NF-κB and SMs can thereby cause production of autocrine TNF.”
BackgroundPhosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Tanzer, M. C., Bludau, I., Stafford, C. A., Hornung, V., & Mann, M. (2021) · Nature Communications · doi:10.1038/s41467-021-26289-6 · Cited by 53
The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases
Shadfar, S., Brocardo, M. G., & Atkin, J. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052484 · Cited by 60
“Importantly, induction of necroptosis is possible only when caspase-8 is inhibited by either pharmacological caspase inhibitors or virally expressed proteins [103].”
BackgroundNecroptosis in acute kidney injury: a shedding light
Wang, S., Zhang, C., Hu, L., & Yang, C. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.37 · Cited by 54
Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases.
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.006 · Cited by 51
Maekawa, T., Kashkar, H., & Coll, N. S. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01060-6 · Cited by 53
“Intriguingly, poxovirus crmA is able to preferentially inhibit caspase-8-mediated apoptosis withoutmarkedly altering caspase-8-mediated inhibition of necroptosis [100].”
BackgroundPost-translational control of RIPK3 and MLKL mediated necroptotic cell death
Murphy, J. M., & Vince, J. E. (2015) · F1000Research · doi:10.12688/f1000research.7046.1 · Cited by 55
Assays for Necroptosis and Activity of RIP Kinases
Degterev, A., Zhou, W., Maki, J. L., & Yuan, J. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-801430-1.00001-9 · Cited by 53
The interplay of autophagy and non-apoptotic cell death pathways
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.004 · Cited by 50
“Another notable negative regulator of necroptosis is Caspase 8, as its activity in the necrosome complex is crucial for determining the particular mechanism by which the cell dies (Oberst et al., 2011).”
BackgroundInfluentialDavidovich, 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
Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6
van Raam, B. J., Ehrnhoefer, D. E., Hayden, M. R., & Salvesen, G. S. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.98 · Cited by 54
Self-citationCell death-based treatment of neuroblastoma
Valter, K., Zhivotovsky, B., & Gogvadze, V. G. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0060-1 · Cited by 53
An emerging role for nanomaterials in increasing immunogenicity of cancer cell death
Mishchenko, T. A., Mitroshina, Е. V., Balalaeva, I. V., Krysko, O., Vedunova, M. V., & Krysko, D. V. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.11.004 · Cited by 53
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
“Under these equi-stoichio-metric apoptosis-inhibitory conditions, FLIP(L) can therefore also inhibit necroptosis [45].”
T Cells and Regulated Cell Death
Spetz, J. K. E., Presser, A. G., & Sarosiek, K. A. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.07.004 · Cited by 55
“Additionally, granzyme B is also able to cleave aspartic acid residues and directly activate caspases (e.g., caspases 3, 7, 8, and 10), inducing apoptosis without the need for MOMP (Ewen et al., 2012; Odake et al., 1991).”
The Role of RIPK1 and RIPK3 in Cardiovascular Disease
DeRoo, E., Zhou, T., & Liu, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218174 · Cited by 47
Dailah, H. G. (2022) · Molecules · doi:10.3390/molecules27217207 · Cited by 51
Cancer cell death: Cell-autonomous and immunogenic dimensions
Galluzzi, L., Kepp, O., Zitvogel, L., Tang, D., & Kroemer, G. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.12.005 · Cited by 59
The cybernetics of TNF: Old views and newer ones
Wallach, D. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.10.014 · Cited by 50
Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death
Douglas, T., & Saleh, M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.014 · Cited by 49
Zhao, Q., Yu, X., Zhang, H., Liu, Y., Zhang, X., Wu, X., Xie, Q., Li, M., Ying, H., & Zhang, H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.011 · Cited by 49
Sun, Y., Li, F., Liu, Y., Qiao, D., Yao, X., Liu, G., Li, D., Xiao, C., Wang, T., & Chi, W. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101263 · Cited by 54
“The elimination of caspase-8 and FADD results in the autonomous activation of RIPK3 and MLKL, initiating the process of necroptosis (Oberst et al., 2011; Tummers et al., 2020; Wang et al., 2008).”
BackgroundMatsuda, I., Matsuo, K., Matsushita, Y., Haruna, Y., Niwa, M., & Kataoka, T. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.506485 · Cited by 51
Cell death programs in Yersinia immunity and pathogenesis
Philip, N. H., & Brodsky, I. E. (2012) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2012.00149 · Cited by 45
“MINI REVIEW ARTICLE published: 30 November 2012 doi: 10.3389/fcimb.2012.00149 Cell death programs in Yersinia immunity and pathogenesis”
BackgroundInfluentialSteinwascher, S., Nugues, A.-L., Schoeneberger, H., & Fulda, S. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.05.020 · Cited by 51
The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair
Ramnath, D., Powell, E. E., Scholz, G. M., & Sweet, M. J. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.014 · Cited by 49
Regulated Cell Death Seen through the Lens of Islet Transplantation
Bruni, A. D. C., Bornstein, S. R., Linkermann, A., & Shapiro, A. M. J. (2018) · Cell Transplantation · doi:10.1177/0963689718766323 · Cited by 48
The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics
Seo, J., Kim, M. W., Bae, K., Lee, S. C., Song, J., & Lee, E. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.012 · Cited by 48
TNF receptor signalling in autoinflammatory diseases
Jarosz-Griffiths, H., Holbrook, J. A., Reyna, S. J. L., & McDermott, M. (2019) · International Immunology · doi:10.1093/intimm/dxz024 · Cited by 46
‘Necrosome’-induced inflammation: must cells die for it?
Wallach, D., Kovalenko, A., & Kang, T. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.07.004 · Cited by 49
Caspase-8 as a Regulator of Tumor Cell Motility
Graf, R. P., Keller, N., Barbero, S., & Stupack, D. G. (2014) · Current Molecular Medicine · doi:10.2174/1566524014666140128111951 · Cited by 48
“The catalytic domains of procaspase-8 and FLIP are shown in light and dark grey, respectively, with the tyrosines indicated in black.”
BackgroundInfluentialKang, J. I., Hong, J.-Y., Choi, J. S., & Lee, S. K. (2016) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2015.145 · Cited by 48
“RIP-3 is important for necroptosis because RIP-3 is modulated by the caspase-8-FLIP complex (Oberst et al., 2011).”
BackgroundSmac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines
Cekay, M., Roesler, S., Frank, T., Knuth, A.-K., Eckhardt, I., & Fulda, S. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.09.002 · Cited by 48
Ye, W., Gunti, S., Allen, C. T., Hong, Y., Clavijo, P. E., Waes, C. V., & Schmitt, N. C. (2020) · OncoImmunology · doi:10.1080/2162402x.2019.1710398 · Cited by 52
Tumor suppressor death-associated protein kinase 1 inhibits necroptosis by p38 MAPK activation
Wu, Y., Chou, T.-F., Young, L., Hsieh, F., Pan, H.-Y., Mo, S.-T., Brown, S. B., Chen, R., Kimchi, A., & Lai, M. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2534-9 · Cited by 49
Bjånes, E., Sillas, R. G., Matsuda, R., Demarco, B., Fettrelet, T., DeLaney, A. A., Kornfeld, O. S., Lee, B. L., Rodriguez-Lopez, E., Grubaugh, D., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009967 · Cited by 53
“Ripk3 mice [95] were a gift of Kim Newton and Vishva Dixit (Genentech) and Ripk3/Casp8 mice [96] were a gift of Doug Green (St.”
Yuan, H., Zhou, L., Chen, Y., You, J., Hu, H., Li, Y., Huang, R., & Wu, S. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2180315 · Cited by 48
Mitochondrial Reactive Oxygen Species and Lytic Programmed Cell Death in Acute Inflammation
Rius‐Pérez, S., Pérez, S., Tolédano, M. B., & Sastre, J. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0209 · Cited by 48
“In complex IIb, activated caspase-8 cleaves and inactivates RIPK1 as well as RIPK3, preventing necroptosis activation (Newton et al., 2019; Oberst et al., 2011).”
Death in the fast lane: what's next for necroptosis?
Oberst, A. (2015) · FEBS Journal · doi:10.1111/febs.13520 · Cited by 47
Self-citationWhat can we learn about stroke from retinal ischemia models?
D’Onofrio, P. M., & Koeberle, P. D. (2012) · Acta Pharmacologica Sinica · doi:10.1038/aps.2012.165 · Cited by 46
A Class of Allosteric Caspase Inhibitors Identified by High-Throughput Screening
Feldman, T., Kabaleeswaran, V., Jang, S. B., Antczak, C., Djaballah, H., Wu, H., & Jiang, X. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.007 · Cited by 48
“…caspase activation possesses cell death-independent biological functions (Li et al., 2010), and caspase activity can regulate necrotic cell death (Oberst et al., 2011), it becomes crucial to develop in vivo and therapeutically amenable caspase inhibitors in order to understand apoptotic and…”
Greve, A., Skals, M., Fagerberg, S. K., Tonnus, W., Ellermann‐Eriksen, S., Evans, R. J., Linkermann, A., & Prætorius, H. A. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00113 · Cited by 46
“Mice lacking both casp8 and RIPK3 are, however, viable (Kaiser et al., 2011; Oberst et al., 2011) and showed similar survival during 6-h observation after iv-injection of ARD6 (high dose, Figure 7A).”
BackgroundSun, Y., Miao, H., Ma, S., Zhang, L., You, C., Tang, F., Cui, Y., Tian, X., Wang, F., Luo, Y. M., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.024 · Cited by 47
Bedell, H. W., Schaub, N. J., Capadona, J. R., & Ereifej, E. S. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.11.017 · Cited by 45
“Caspase 8 can prevent necroptosis [96], regulate cytokine transcription, and is a negative regulator of inflammasomes [97].”
Background
Metadata
- Authors
- Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Nature
- Published
- 2011-03-02
- Volume
- 471
- Issue
- 7338
- Pages
- 363-367
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3077893
- OpenAlex
- W1975593978
- Cited by
- 1,278
- References
- 32
- Citations by year
- 2026: 49 · 2025: 68 · 2024: 84 · 2023: 69 · 2022: 88 · 2021: 81 · 2020: 88 · 2019: 71 · 2018: 87 · 2017: 80 · 2016: 102 · 2015: 83 · 2014: 116 · 2013: 81 · 2012: 81
- FWCI
- 42.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ariad Pharmaceuticals
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute (P01CA069381)
- National Institute of Allergy and Infectious Diseases (R01AI044828, R37AI044828)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- caspase-8, RIPK3, necroptosis, apoptosis, death receptors, Fas, embryonic lethality, Fas ligand, TNF-alpha resistance, cell death regulation, proteolytic complex, lymphocyte activation
- MeSH terms
- Animals, Cell Line, Female, Male, Necrosis, Phenotype, Tumor Necrosis Factor-alpha, Viral Proteins, Serpins, Apoptosis, fas Receptor, Multiprotein Complexes, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, CASP8 and FADD-Like Apoptosis Regulating Protein, Biocatalysis, Caspase Inhibitors
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