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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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Kolb, J. P., Oguin, T. H., Oberst, A., & Martinez, J. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.06.009 · Cited by 136
“This morphology stands in clear contrast to that of apoptosis (discussed above), and has led to the idea that necroptosismediated DAMP release renders this cell death program uniquely inflammatory [21].”
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“To define the role of caspase-8 in this pathway, we used Casp8Rip3 mice, which are viable (29, 30), in contrast to the embryonically lethal Casp8 (28).”
BackgroundMethodSelf-citationCaspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock
Mandal, P., Feng, Y., Lyons, J. D., Berger, S. B., Otani, S., DeLaney, A. A., Tharp, G. K., Maner-Smith, K. M., Burd, E. M., Schaeffer, M. C., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.06.011 · Cited by 131
“Independently derived Casp8Ripk3 mice (Oberst et al., 2011) also resisted while littermate Casp8Ripk3 controls succumbed (Figure S1A).”
The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease
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The Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense
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“However, under most physiological settings this signaling is antagonized by the caspase-8/cFLIP complex (40, 41), which is recruited to the necrosome via interactions between the adapter FADD and Snyder and Oberst Page 4”
BackgroundSelf-citationSharma, B. R., Karki, R., Rajesh, Y., & Kanneganti, T. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105141 · Cited by 134
IAP Family of Cell Death and Signaling Regulators
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“5, cells are sensitized to necrotic cell death, in response to DR activity (Varfolomeev et al., 1998; Kaiser et al., 2011; Oberst et al., 2011), uncovering a role”
InfluentialLopez, J. S., John, S. W., Tenev, T., Rautureau, G. J. P., Hinds, M. G., Francalanci, F., Wilson, R., Broemer, M., Santoro, M. M., Day, C. L., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.008 · Cited by 125
“Recent genetic data indicate that FADD, caspase-8 and FLIP are required to regulate RIP1/3 (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011).”
BackgroundLee, S. H., Kwon, J. Y., Kim, S. Y., Jung, K., & Cho, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-09767-0 · Cited by 137
Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP
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A long-awaited merger of the pathways mediating host defence and programmed cell death
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Apoptosis Initiation Through the Cell-Extrinsic Pathway
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Caspase‐8: not so silently deadly
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Targeting Neutrophils for Promoting the Resolution of Inflammation
Filep, J. G. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.866747 · Cited by 131
“Caspase-8 forms a complex with FLIP (FLICE-inhibitory protein), which inhibits RIPK3-dependent necrosis and prevents degranulation (32, 33).”
BackgroundThe regulation of necroptosis by post-translational modifications
Meng, Y., Sandow, J. J., Czabotar, P. E., & Murphy, J. M. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-020-00722-7 · Cited by 130
The role of apoptosis in megakaryocytes and platelets
Kile, B. T. (2014) · British Journal of Haematology · doi:10.1111/bjh.12757 · Cited by 122
“…regulate each other is still largely unexplored, there are clearly some profoundly important interactions between key components, e.g. the requirement for caspase-8 in suppressing RIPK3dependent necroptosis during embryonic development (Kaiser et al, 2011; Oberst et al, 2011; Zhang et al, 2011).”
BackgroundIn vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity
Tang, H. L., Tang, H. M., Fung, M. C., & Hardwick, J. M. (2015) · Scientific Reports · doi:10.1038/srep09015 · Cited by 115
Exploiting poly(I:C) to induce cancer cell apoptosis
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“partial activation of caspase-8 prevents complete cleavage of RIP1, resulting in cell survival.(34,35) Paone et al.”
BackgroundGullett, J. M., Tweedell, R. E., & Kanneganti, T. (2022) · Cells · doi:10.3390/cells11091495 · Cited by 129
Steinhart, L., Belz, K., & Fulda, S. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.320 · Cited by 124
“For example, caspase activity has been shown to negatively regulate necroptosis by cleaving RIP1, one of the critical regulators of necroptosis.(11) This implies that necroptosis serves as a fail-safe and even more efficient cell death”
BackgroundAccumulation of Cytosolic Calcium Induces Necroptotic Cell Death in Human Neuroblastoma
Nomura, M., Ueno, A., Saga, K., Fukuzawa, M., & Kaneda, Y. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1283 · Cited by 119
A new kind of cell suicide: mechanisms and functions of programmed necrosis
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RIPK 3 in cell death and inflammation: the good, the bad, and the ugly
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“When the activity of this heterodimeric complex is completely inhibited, either by pharmacological inhibition of caspase-8 or when the complex contains cFLIPs (short isoform), the suppression of RIP1 and RIP3 is relieved; RIP1 then phosphorylates RIP3 which regulates an incompletely understood necroptotic signaling ca…”
BackgroundMoriwaki, K., Farias Luz, N., Balaji, S., De Rosa, M. J., O’Donnell, C. L., Gough, P. J., Bertin, J., Welsh, R. M., & Chan, F. K.-M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501662 · Cited by 116
Programmed necrosis in acute kidney injury
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“Consequently, it will be interesting to investigate RIP3-deficient mice in direct comparison with caspase-8/RIP3 double-deficient mice [48, 49] in AKI models.”
BackgroundNETs: the missing link between cell death and systemic autoimmune diseases?
Darrah, E., & Andrade, F. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00428 · Cited by 120
“Necroptosis may play a regulatory role in the development of the immune system and in the response to viral infection by serving as a backup mechanism of cell death if apoptosis is impaired (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011; Mocarski et al., 2012).”
BackgroundTargeting extrinsic apoptosis in cancer: Challenges and opportunities
Fulda, S. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.01.006 · Cited by 119
Necroptosis: Pathway diversity and characteristics
de Almagro, M. C., & Vucic, D. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.02.002 · Cited by 118
Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway
Duan, Y.-W., Chen, S., Li, Q., & Zang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137191 · Cited by 117
Darding, M., & Meier, P. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.163 · Cited by 118
“While caspase-8- and FADD-deficient mice die at embryonic stage 10.5, they are rescued, at least in part, by co-deletion of RIPK1 and RIPK3.”
BackgroundInfluentialLi, L., Chen, Y., Doan, J., Murray, J. D., Molkentin, J. D., & Liu, Q. (2014) · Circulation · doi:10.1161/circulationaha.114.011195 · Cited by 112
RIP1-Dependent and Independent Effects of Necrostatin-1 in Necrosis and T Cell Activation
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“In addition to TNF-like death cytokines, RIP1/ RIP3-dependent necrosis also contributes to the abortive embryonic development and impaired T lymphocyte proliferation of FADD and caspase-8 mice [9,10,11,12,13].”
BackgroundCellular FLICE-like inhibitory proteins (c-FLIPs): Fine-tuners of life and death decisions
Öztürk, S., Schleich, K., & Lavrik, I. N. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.01.019 · Cited by 116
RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development
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The in vivo evidence for regulated necrosis
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“CASP- 8ko Dko with RIPK3 or MLKL Reversal of lethal phenotype (4, 47)”
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“However, necroptosis occurs when caspase 8 is inhibited (Oberst et al., 2011).”
BackgroundThe pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils
D’Cruz, A. A., Speir, M., Bliss‐Moreau, M., Dietrich, S., Wang, S., Chen, A. A., Gavillet, M., Al‐Obeidi, A., Lawlor, K. E., Vince, J. E., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aao1716 · Cited by 114
Self-citationComparing the effects of different cell death programs in tumor progression and immunotherapy
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Self-citationIntegration of innate immune signalling by caspase-8 cleavage of N4BP1
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Multitasking Kinase RIPK1 Regulates Cell Death and InflammationPreprint
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“Mice lacking caspase-8 or FADD also die around E11 (Varfolomeev et al. 1998; Yeh et al. 1998), but only need to lose RIPK3 or MLKL to be viable (Kaiser et al. 2011; Oberst et al. 2011; AlvarezDiaz et al. 2016; Zhang et al. 2016).”
BackgroundmiR-874 regulates myocardial necrosis by targeting caspase-8
Wang, K., Liu, F., Zhou, L.-Y., Ding, S.-L., Long, B., Liu, C.-Y., Sun, T., Fan, Y.-Y., Sun, L., & Li, P.-F. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.233 · Cited by 110
“In L929 cells, treatment with caspase inhibitor alone has been shown to cause RIPK3-dependent death.(26) Caspase-8 can cleave both RIPK1 and RIPK3, inhibiting their role in caspase-independent cell death.”
BackgroundMethodStaurosporine Induces Necroptotic Cell Death under Caspase-Compromised Conditions in U937 Cells
Dunai, Z. A., Imre, G., Barna, G., Korcsmáros, T., Peták, I., Bauer, P. I., & Mihalik, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041945 · Cited by 109
“The size of the fragment is in accordance with the caspase-8-mediated cleavage of RIPK1 [51].”
BackgroundResearch trends, hot spots and prospects for necroptosis in the field of neuroscience
Xiong, K., Yan, W., Lu, S., Yang, Y., Ning, W.-Y., Cai, Y., Hu, X.-M., & Zhāng, Q. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.303032 · Cited by 107
“One is by promoting cFLIP recruitment of caspase-8, causing caspase-8 inactivation (Oberst et al., 2011).”
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Interplay between Cell Death and Cell Proliferation Reveals New Strategies for Cancer Therapy
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CaMKII is a nodal signal for multiple programmed cell death pathways in heart
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“It is important to note that developmental consequences of mutant ripoptosome components only show modest dependence on TNF signaling despite the fact that canonical, RIP1-dependent activation of RIP3 kinase activity and RHIM signal transduction are crucial to the demise of mutant mice (Cho et al., 2009; Kaiser et al.…”
BackgroundInfluentialProtease signaling in animal and plant‐regulated cell death
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Self-citationCurrent translational potential and underlying molecular mechanisms of necroptosis
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Yu, H., Yang, B., Yang, J., Shi, X., Yang, X., Zhang, D., Zhao, D., Yan, W., Chen, L., Zheng, H., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810224 · Cited by 106
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Role of Apoptosis in Colon Cancer Biology, Therapy, and Prevention
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The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance
Gautheron, J., Vucur, M., Schneider, A. T., Severi, I., Roderburg, C., Roy, S., Bartneck, M., Schrammen, P. L., Díaz, M. B., Ehling, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11869 · Cited by 106
Self-citationThe Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis
Moriwaki, K., & Chan, F. K.-M. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.08.007 · Cited by 107
“Because TRIF is also a RHIM-containing adaptor, it is tantalizing to speculate that TRIF recruits and activates RIPK1 and RIPK3 through RHIM-RHIM interaction.”
BackgroundInfluentialLegarda, D., Justus, S. J., Ang, R. L., Rikhi, N., Li, W., Moran, T. M., Zhang, J., Mizoguchi, E., Zelic, M., Kelliher, M. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.032 · Cited by 104
“To confirm that the FADD/CASPASE-8 complex cleaves CYLD in macrophages, we compared BMDMs from Ripk3 / Casp8 / or Ripk3 / Fadd / mice toRipk3 / mice since theRipk3 deletion rescued the embryonic lethality of the Casp8 / and Fadd / single knockout mice (Dillon et al., 2012; Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundZou, J., Kawai, T., Tsuchida, T., Kozaki, T., Tanaka, H., Shin, K.-S., Kumar, H., & Akira, S. (2013) · Immunity · doi:10.1016/j.immuni.2012.12.007 · Cited by 103
“, 2011), suggesting that caspase 8 negatively regulates necroptosis, probably by cleaving RIP-1 and/or RIP3 (Feng et al., 2007; Feoktistova et al., 2011; Lin et al., 1999; Oberst et al., 2011; Rajput et al., 2011).”
BackgroundRoderick, J. E., Hermance, N. M., Zelic, M., Simmons, M. J., Polykratis, A., Pasparakis, M., & Kelliher, M. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409389111 · Cited by 101
“For example, the FADD/caspase-8/FLICE-like inhibitory protein long form (FLIPL) complex regulates RIPK1 and RIPK3 activity during development, because the embryonic lethality associated with a caspase-8 deficiency is completely rescued by the absence of RIPK3 (19, 20).”
BackgroundLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
Taraborrelli, L., Peltzer, N., Montinaro, A., Kupka, S., Rieser, E., Hartwig, T., Sarr, A., Darding, M., Dráber, P., Haas, T. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06155-8 · Cited by 103
Gielecińska, A., Kciuk, M., Yahya, E. B., Ainane, T., Mujwar, S., & Kontek, R. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.189024 · Cited by 110
GRIM-19 Mediated Translocation of STAT3 to Mitochondria is Necessary for TNF Induced Necroptosis.
Shulga, N., & Pastorino, J. G. (2012) · Journal of Cell Science · doi:10.1242/jcs.103093 · Cited by 101
“Remarkably, activated caspase-8 cleaves and inactivates RIPK-1 and 3, eventuating in apoptosis (Oberst et al., 2011).”
RetractedTAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation
Morioka, S., Broglie, P. M., Omori, E., Ikeda, Y., Takaesu, G., Matsumoto, K., & Ninomiya‐Tsuji, J. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201305070 · Cited by 101
“Inhibition of caspases by gene deletion of either caspase-8 or its adaptor protein FADD causes RIPK1–RIPK3-dependent cell death (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011).”
Jondle, C. N., Gupta, K., Mishra, B. B., & Sharma, J. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1007338 · Cited by 102
Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases
Lawlor, K. E., Murphy, J. M., & Vince, J. E. (2024) · Immunity · doi:10.1016/j.immuni.2024.02.011 · Cited by 108
Laukens, B., Jennewein, C., Schenk, B., Vanlangenakker, N., Schier, A., Cristofanon, S., Zobel, K., Deshayes, K., Vucic, D., Jeremias, I., et al. (2011) · Neoplasia · doi:10.1593/neo.11610 · Cited by 101
“Accordingly, key components of the extrinsic apoptosis pathway including FADD and caspase-8 were shown to exert also nonapoptotic functions by preventing programmed necrosis [30–32].”
BackgroundMitochondrial injury and dysfunction in hypertension-induced cardiac damage
Eirin, A., Lerman, A., & Lerman, L. O. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu436 · Cited by 100
Manipulation of apoptosis and necroptosis signaling by herpesviruses
Guo, H., Kaiser, W. J., & Mocarski, E. S. (2015) · Medical Microbiology and Immunology · doi:10.1007/s00430-015-0410-5 · Cited by 99
“The potency and delicate balance of apoptotic and necrotic pathways was first brought to light in studies that revealed a RIP1–RIP3-dependent process dictating midgestational embryonic lethality of Casp8-deficient mice [34, 35] and FADD-deficient mice [36, 37].”
BackgroundBAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages
Chauhan, D., Bartok, E., Gaidt, M. M., Bock, F. J., Herrmann, J. E., Seeger, J. M., Brož, P., Beckmann, R., Kashkar, H., Tait, S. W. G., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.087 · Cited by 103
Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice
Belizário, J. E., Cordeiro, L., & Enns, S. C. (2015) · Mediators of Inflammation · doi:10.1155/2015/128076 · Cited by 106
Lamothe, B., Lai, Y., Xie, M., Schneider, M. D., & Darnay, B. G. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.01225-12 · Cited by 99
“Furthermore, our study indicates that the deregulation of TAK1 expression leads to apoptosis and necroptosis, which raises the question of whether the cell inflammation and cell death observed in some conditional TAK1-deficient mice could be attenuated by the simultaneous deletion of caspase-8 and RIP3 genes (38, 39).”
BackgroundLiu, W., Chen, B., Wang, Y., Meng, C., Huang, H., Huang, X., Qin, J., Mulay, S. R., Anders, H., Qiu, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1716959115 · Cited by 99
“Critical for the formation of the necroposome is a comprised caspase-8 activity (55, 56).”
BackgroundLi, X., Zhang, M., Huang, X., Liang, W. P., Li, G., Lu, X., Li, Y., Pan, H., Shi, L., Zhu, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19935-y · Cited by 99
Macrophage and neutrophil death programs differentially confer resistance to tuberculosis
Stutz, M. D., Allison, C. C., Ojaimi, S., Preston, S., Doerflinger, M., Arandjelovic, P., Whitehead, L. W., Bader, S. M., Batey, D., Asselin-Labat, M.-L., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.06.009 · Cited by 100
TRAF2 is a biologically important necroptosis suppressor
Petersen, S. L., Chen, T. T., Lawrence, D. A., Marsters, S. A., Gonzalvez, F., & Ashkenazi, A. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2015.35 · Cited by 99
Gonçalves, A. V., Margolis, S. R., Quirino, G. F. S., Mascarenhas, D. P. A., Rauch, I., Doyle, R. N., Ansaldo, E., Fontana, M. F., Vance, R. E., & Zamboni, D. S. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007886 · Cited by 97
Kiss, M., Walle, L. V., Saavedra, P. H. V., Lebegge, E., Damme, H. V., Murgaski, A., Qian, J., Ehling, M., Pretto, S., Bolli, E., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0431 · Cited by 98
“Hence, we assessed the contribution of caspase-8 to IL1b release and neutrophil recruitment in tumors by usingRipk3 / Casp8 / mice, inwhichRipk3 deletion rescues embryonic lethality caused by caspase-8 deficiency (42).”
Wu, W., Wang, X., Sun, Y., Berleth, N., Deitersen, J., Schlütermann, D., Stuhldreier, F., Hieke, N., Mendiburo, M. J., Cox, J., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1899667 · Cited by 98
Therapeutic exploitation of necroptosis for cancer therapy
Fulda, S. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.07.002 · Cited by 97
Necroptosis-independent signaling by the RIP kinases in inflammation
Moriwaki, K., & Chan, F. K.-M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2203-4 · Cited by 99
Single cell analysis of PANoptosome cell death complexes through an expansion microscopy method
Wang, Y., Nagakannan, P., Han, J., Sundaram, B., Lee, S., Karki, R., Guy, C. S., & Kanneganti, T. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04564-z · Cited by 100
Immunological consequences of kidney cell death
Sarhan, M., von Mäßenhausen, A., Hugo, C., Oberbauer, R. W., & Linkermann, A. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0057-9 · Cited by 100
Necroptosis restricts influenza A virus as a stand-alone cell death mechanism
Shubina, M., Tummers, B., Boyd, D. F., Zhang, T., Yin, C., Gautam, A., Guo, X.-Z. J., Rodríguez, D. A., Kaiser, W. J., Vogel, P., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191259 · Cited by 96
“We produced Casp8 knock-in mice (Casp8DA) in which the initiation site for autoproteolytic processing of Casp8, essential for its capacity to stimulate apoptosis, was abolished by mutation of a critical aspartic acid to alanine (D387A; Fig. 1 B and Fig. S1, A and B; Kang et al., 2008; Oberst et al., 2011; Philip et al…”
BackgroundSelf-citationZhang, X., Fan, C., Zhang, H., Zhao, Q., Liu, Y., Xu, C., Xie, Q., Wu, X., Yu, X., Zhang, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.103 · Cited by 93
“…to Ripk3 / Fadd / Mice In all settings where Caspase-8 or Fadd deficiency has been rescued by elimination of Ripk3 or the kinase activity of RIPK3, resulting viable mice exhibit lymphoid hyperplasia as they age (Dillon et al., 2012; Kaiser et al., 2011; Newton et al., 2014; Oberst et al., 2011).”
InfluentialCaspase Allostery and Conformational Selection
Clark, A. C. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00540 · Cited by 95
PANoptosis in Viral Infection: The Missing Puzzle Piece in the Cell Death Field
Nguyen, L. N., & Kanneganti, T. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167249 · Cited by 100
“The formation of the RIPK1-RIPK3 necrosome complex, in most physiological conditions, is inhibited by the cFLIP/caspase-8 heterodimeric complex, which is recruited to the RIPK1-RIPK3 complex through the adaptor FADD and can cleave both RIPK1 and RIPK3 to prevent necroptosis and promote apoptosis (Figure 3).(103,104,10…”
The evolution of regulated cell death pathways in animals and their evasion by pathogens
Tummers, B., & Green, D. R. (2021) · Physiological Reviews · doi:10.1152/physrev.00002.2021 · Cited by 95
Self-citationLinear ubiquitination at a glance
Spit, M., Rieser, E., & Walczak, H. (2019) · Journal of Cell Science · doi:10.1242/jcs.208512 · Cited by 94
“After dissociation from complex I, RIPK1 recruits the Fas-associated death domain protein (FADD), caspase-8, cellular FLICE-like inhibitory protein (cFLIP, also known as CFLAR), RIPK3 and mixed lineage kinase domain-like protein (MLKL) (Feoktistova et al., 2011; He et al., 2009; Oberst et al., 2011; Sun et al., 2012;…”
BackgroundCaspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
Fricker, M., Vilalta, A., Tolkovsky, A. M., & Brown, G. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.427880 · Cited by 92
Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
Volk, A. G., Li, J., Xin, J., You, D., Zhang, J., Liu, X., Xiao, Y., Breslin, P., Li, Z., Wei, W., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20130990 · Cited by 94
“, 2009; Vallabhapurapu and Karin, 2009), whereas the TNF-induced death signal is driven by caspase-8–dependent apoptosis or RIP1/3-dependent necroptosis (Wang et al., 2008; He et al., 2009; Zhang et al., 2009, 2011; Feoktistova et al., 2011; Günther et al., 2011; Kaiser et al., 2011; Oberst et al., 2011; Tenev et al.,…”
Programmed Cell Death in Sepsis Associated Acute Kidney Injury
Wu, Z., Deng, J., Zhou, H., Tan, W., Lin, L., & Yang, J. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.883028 · Cited by 99
“The negative regulator of necroptosis is caspase-8 (134).”
BackgroundPhilip, N. H., DeLaney, A. A., Peterson, L. W., Santos-Marrero, M., Grier, J. T., Sun, Y., Wynosky-Dolfi, M. A., Zwack, E. E., Hu, B., Olsen, T. M., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005910 · Cited by 89
Self-citation
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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