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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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BackgroundApoptotic cell death in disease—Current understanding of the NCCD 2023
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Self-citationRegulated necrosis in kidney ischemia-reperfusion injury
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Apoptosis and Necrosis in the Liver
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“…that the cFLIP L :caspase 8 heterodimer has a different substrate specificity than the caspase 8:caspase 8 homodimer, and is involved in executing the nonapoptotic functions of caspase-8, specifically, the inhibition of receptor interacting kinase-3 (RIPK or RIP-3)-dependent necrosis (163,272).”
RIP3: a molecular switch for necrosis and inflammationPreprint
Moriwaki, K., & Chan, F. K.-M. (2013) · Genes & Development · doi:10.1101/gad.223321.113 · Cited by 364
“Moreover, caspase-8 / RIP3 / mice developed lpr/ gld-like lymphoproliferation and lupus-like disease (Oberst et al. 2011).”
BackgroundResultKarki, R., Lee, S., Mall, R., Nagakannan, P., Wang, Y., Sharma, B. R., Malireddi, R. K. S., Yang, D., Trifkovic, S., Steele, J. A., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abo6294 · Cited by 349
Caspases Connect Cell-Death Signaling to Organismal Homeostasis
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“Because excessive necrosis in FADD- or caspase-8-deficient mice was rescued by inactivation of RIPK1 or RIPK3 (28, 44, 45), FADD and caspase-8 are paradoxically prosurvival factors during development.”
BackgroundNecroptosis in development and diseasesPreprint
Shan, B., Pan, H., Najafov, A., & Yuan, J. (2018) · Genes & Development · doi:10.1101/gad.312561.118 · Cited by 352
“…long isoform FLIPL forms a heterodimeric complex with caspase-8 in which the latter is partially active and inhibits RIPK1-dependent cell death (Oberst et al. 2011), short isoform FLIPS forms caspase-8 heterodimers completely devoid of catalytic activity, promoting RIPK1 kinase activation and…”
BackgroundDickens, 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
MicroRNAs in apoptosis, autophagy and necroptosis
Su, Z., Yang, Z., Xu, Y., Chen, Y., & Yu, Q. (2015) · Oncotarget · doi:10.18632/oncotarget.3523 · Cited by 350
“However, this cFLIPL-caspase-8 heterodimer retains the ability to cleave RIP1, which blocks RIP1–RIP3 formation and necroptosis [145].”
BackgroundBonora, M., Wieckowski, M. R., Chinopoulos, C., Kepp, O., Kroemer, G., Galluzzi, L., & Pinton, P. (2015) · Oncogene · doi:10.1038/onc.2014.96 · Cited by 330
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Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
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Survival Function of the FADD-CASPASE-8-cFLIPL Complex
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“Formally, the ability of RIPK3 ablation to rescue development of caspase-8−/− (Kaiser et al., 2011; Oberst et al., 2011) or FADD−/− mice (Figure 1), but not that of FLIP−/− mice (Figure 2), indicates that FLIP has a function distinct from those of FADD and caspase-8 in embryogenesis.”
BackgroundInfluentialSelf-citationCell Death in the Lung: The Apoptosis–Necroptosis Axis
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“RIPK3 expression is increased in IPF alveolar epithelial cells, and Ripk3-deficient mice have attenuated fibrosis and decreased HMGB1 in a bleomycin model of IPF (127).”
BackgroundInfluentialCell death pathways: intricate connections and disease implications
Kist, M., & Vucic, D. (2021) · The EMBO Journal · doi:10.15252/embj.2020106700 · Cited by 337
“Heterodimers of c-FLIP and caspase-8 partially activate caspase-8 and restrict necroptosis by cleaving RIP1 (at Asp324 human or at Asp325 mouse RIP1) (Oberst et al , 2011; Pop et al , 2011).”
The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis
Goodall, M. L., Fitzwalter, B. E., Zahedi, S., Wu, M., Rodriguez, D., Mulcahy-Levy, J. M., Green, D. R., Morgan, M., Cramer, S. D., & Thorburn, A. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.04.018 · Cited by 314
“For instance, repression of the necroptotic pathway by apoptotic regulators, such as FADD and caspase-8, is essential for proper mammalian development (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011).”
BackgroundSelf-citationMoquin, D. M., McQuade, T., & Chan, F. K.-M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076841 · Cited by 320
“necrosis during embryonic development [7-9], to enforce”
Sphingolipid lysosomal storage disorders
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MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
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“This inhibits formation of complex-II and the necrosome by cleaving RIPK1, RIPK3, and CYLD (Feng et al., 2007; Lin et al., 1999; O’Donnell et al., 2011; Oberst et al., 2011).”
BackgroundRIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
Takahashi, N., Vereecke, L., Bertrand, M. J. M., Duprez, L., Berger, S. B., Divert, T., Gonçalves, A., Sze, M., Gilbert, B., Kourula, S., et al. (2014) · Nature · doi:10.1038/nature13706 · Cited by 318
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“For example, inhibition of the RIP1/RIP3 complex by caspase 8 has recently been suggested as one possible mechanism protecting cells from necroptosis.(22,23) The need of RIP3 overexpression Figure 4 RIP3 is up-regulated in ischaemic hearts.”
BackgroundRegulation of alveolar macrophage death in acute lung inflammation
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The clearance of dying cells: table for two
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“Mice deficient in caspase-8 are embryonic lethal 19-21 , and this lethality is rescued by further deleting the necroptosis-regulating kinase RIP3 22,23 .”
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“To generate cyclophilinD-KO/caspase-8 HET mice, we crossed cyclophilin D-KO mice (B6;129-Ppif tm1Jmol/J, order no. 009071; The Jackson Laboratory; described in Nakayama et al., 2007) with caspase-8/RIPK3-DKO mice (Oberst et al., 2011; see also Supplemental Experimental Procedures).”
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RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis
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“caspase-8 can suppress this activation.(25,26) We tested”
BackgroundSelf-citationViral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways
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“These data indicate a vital role for caspase-8 in suppressing necroptosis by targeting a component of the RIP3 pathway (8, 9).”
BackgroundBonnet, M. C., Preukschat, D., Welz, P.-S., van Loo, G., Ermolaeva, M. A., Bloch, W., Haase, I., & Pasparakis, M. (2011) · Immunity · doi:10.1016/j.immuni.2011.08.014 · Cited by 295
“embryonic lethality of caspase-8-deficient mice, and mice lacking both caspase-8 and RIP3 are born normally and reach adulthood without displaying any abnormalities apart from the lymphoproliferative disease characteristic of Fas deficiency (Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundRoles of Caspases in Necrotic Cell Death
Yuan, J., Najafov, A., & Py, B. F. (2016) · Cell · doi:10.1016/j.cell.2016.11.047 · Cited by 299
Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium
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“In contrast to pyroptosis mediated by caspase-1, Z-VAD-FMK promotes necroptosis by preventing caspase-8 from functioning as a negative regulator of RIPK1/3 signaling (Hitomi et al., 2008; Kaiser et al., 2011; Oberst et al., 2011).”
RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition
Kaiser, W. J., Daley-Bauer, L. P., Thapa, R. J., Mandal, P., Berger, S. B., Huang, C., Sundararajan, A., Guo, H., Roback, L., Speck, S. H., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401857111 · Cited by 291
“RIP1 remains a component of a death receptor-free cytosolic complex, termed complex II (also called the ripoptosome) (1–3), together with FADD, Casp8, and cFLIP where cFLIP levels control Casp8 activation (13) and death (14).”
BackgroundProgramming inflammatory cell death for therapy
Christgen, S. L., Tweedell, R. E., & Kanneganti, T. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108010 · Cited by 298
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“reciprocal regulations? Caspase-8-c-FLIP heterodimer is known to be the key modulator for inhibition of necroptosis.(51,54,98,99) Deletion of c-Flip causes embryonic lethality with blood vessel abnormality similar to deletion of caspase-8 or of Tak1 (Table 1).”
BackgroundOnizawa, M., Oshima, S., Schulze-Topphoff, U., Oses-Prieto, J. A., Lu, T., Tavares, R., Prodhomme, T., Duong, B., Whang, M. I., Advincula, R., et al. (2015) · Nature Immunology · doi:10.1038/ni.3172 · Cited by 284
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RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4
Najjar, M., Saleh, D., Zelic, M., Nogusa, S., Shah, S., Tai, A., Finger, J. N., Polykratis, A., Gough, P. J., Bertin, J., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.007 · Cited by 292
“…more sensitive and specific methods, especially to assess caspase-8 activity in necroptosis-inhibiting caspase-8 and FLIPL heterodimeric complex (Oberst et al., 2011), are needed to further address this question in LPS-induced and other in vivo models of RIPK1 and RIPK3 kinase regulation.”
Philip, N. H., Dillon, C. P., Snyder, A. G., Fitzgerald, P., Wynosky-Dolfi, M. A., Zwack, E. E., Hu, B., Fitzgerald, L. M., Mauldin, E. A., Copenhaver, A. M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403252111 · Cited by 275
“Caspase-8 catalytic activity prevents a lethal RIPK3-dependent programmed necrosis that occurs in early embryonic development (23).”
BackgroundSelf-citationCell death and inflammation during obesity: “Know my methods, WAT(son)”
Hildebrandt, X., Ibrahim, M. A., & Peltzer, N. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01062-4 · Cited by 307
Schwarzer, R., Jiao, H., Wachsmuth, L., Tresch, A., & Pasparakis, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.002 · Cited by 280
“FADD-mediated activation of caspase-8 is essential for death receptor-induced apoptosis, but also for inhibiting receptor interacting protein kinase 3 (RIPK3)-MLKL-dependent necroptosis, as shown by the rescue of the embryonic lethality of Fadd-/- or Casp8-/- mice by crossing to Ripk3-/- or Mlkl-/animals (Alvarez-Diaz…”
Dimberg, L. Y., Anderson, C. K., Camidge, D. R., Behbakht, K., Thorburn, A. M., & Ford, H. L. (2012) · Oncogene · doi:10.1038/onc.2012.164 · Cited by 280
Ferroptosis and Necroptosis in the Kidney
Belavgeni, A., Meyer, C., Stumpf, J., Hugo, C., & Linkermann, A. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.016 · Cited by 286
Henry, C. M., & Martin, S. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.022 · Cited by 267
“…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).”
BackgroundRegulated Cell Death: Signaling and Mechanisms
Ashkenazi, A., & Salvesen, G. S. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100913-013226 · Cited by 289
Self-citationHe, J., Liu, D., Zhao, L., Zhou, D., Rong, J., Zhang, L., & Xia, Z. (2022) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2022.11357 · Cited by 287
Karki, R., Man, S. M., Malireddi, R. K. S., Gurung, P., Vogel, P., Lamkanfi, M., & Kanneganti, T.-D. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.01.006 · Cited by 272
“Mice Aim2 / , Nlrp3 / , Asc / , Casp1 / Casp11 / , Casp11 / , Casp1 / Casp11, Nlrc4 / , Nod1 / , Il1b / , Il18 / , Rip3 / , Rip3 / Casp8 / , and Rip3 / Fadd / mice were described previously (Jones et al., 2010; Kanneganti et al., 2006; Kayagaki et al., 2011; Mariathasan et al., 2004, 2006; Oberst et al., 2011; Shornic…”
BackgroundTumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects
Gough, P., & Myles, I. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.585880 · Cited by 288
“After activation of caspase 8 in Complex IIa and IIb, RIPK1 and RIPK3 are degraded by the activated caspase in the cytosol (46, 47).”
BackgroundA Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development
Lin, J., Li, H., Yang, M. H., Ren, J., Huang, Z., Han, F., Huang, J., Ma, J., Zhang, D., Zhang, Z., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2012.12.012 · Cited by 266
Chen, W., Zhou, Z., Li, L., Zhong, C., Zheng, X., Wu, X., Zhang, Y., Ma, H., Huang, D., Li, W., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.435545 · Cited by 272
Concepts of tissue injury and cell death in inflammation: a historical perspective
Wallach, D., Kang, T., & Kovalenko, A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3561 · Cited by 266
Hughes, 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
“Hence, during both development and immune cell proliferation, c-FLIPL:procaspase-8 heterodimers function to inhibit RIPK1RIPK3-mediated programmed necrosis (Oberst et al., 2011).”
InfluentialTNFR1-dependent cell death drives inflammation in Sharpin-deficient mice
Rickard, J. A., Anderton, H., Etemadi, N., Nachbur, U., Darding, M., Peltzer, N., Lalaoui, N., Lawlor, K. E., Vanyai, H. K., Hall, C. M., et al. (2014) · eLife · doi:10.7554/elife.03464 · Cited by 270
“Ripk3 deletion prevents the embryonic lethality seen with either Fadd or Casp8 deletion and the mice survive to adulthood (Kaiser et al., 2011; Oberst et al., 2011; Dillon et al., 2012).”
BackgroundInfluentialTumor Promotion via Injury- and Death-Induced Inflammation
Kuraishy, A. I., Karin, M., & Grivennikov, S. I. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.006 · Cited by 270
Molecular mechanisms of regulated necrosis
Galluzzi, L., Kepp, O., Krautwald, S., Kroemer, G., & Linkermann, A. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.02.006 · Cited by 258
“At least in part, such feedback circuitries are responsible for the delayed discovery of RN, which in a vast number of experimental settings is actively blocked by caspase-8/FLIPL/FADD [42-47].”
BackgroundProgrammed Cell Death: Molecular Mechanisms and Implications for Safety Assessment of Nanomaterials
Andón, F. T., & Fadeel, B. (2012) · Accounts of Chemical Research · doi:10.1021/ar300020b · Cited by 257
HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death
Peltzer, N., Rieser, E., Taraborrelli, L., Draber, P., Darding, M., Pernaute, B., Shimizu, Y., Sarr, A., Draberova, H., Montinaro, A., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.066 · Cited by 257
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 263
Self-citationCaspase-8: The double-edged sword
Mandal, R., Compte, J., Kostova, I., Becker, S., & Strebhardt, K. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188357 · Cited by 261
Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis
Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J. (2017) · The EMBO Journal · doi:10.15252/embj.201796476 · Cited by 237
“Cells can be sensitised to RIPK3-dependent necroptosis by genetic loss (Kaiser et al , 2011; Oberst et al , 2011) or chemical blockade of caspase-8 (Vandenabeele et al , 2006).”
Photoreceptor cell death and rescue in retinal detachment and degenerations
Murakami, Y., Notomi, S., Hisatomi, T., Nakazawa, T., Ishibashi, T., Miller, J. W., & Vavvas, D. G. (2013) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2013.08.001 · Cited by 255
“However, in order to avoid confusion, we here express it descriptively as ‘RIP kinasedependent necrosis’ according to recent studies (Green et al., 2011; Oberst et al., 2011).”
InfluentialDetermination of apoptotic and necrotic cell death in vitro and in vivo
Berghe, T. V., Grootjans, S., Goossens, V., Dondelinger, Y., Krysko, D. V., Takahashi, N., & Vandenabeele, P. (2013) · Methods · doi:10.1016/j.ymeth.2013.02.011 · Cited by 258
Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors
Canli, Ö., Alankuş, Y. B., Grootjans, S., Vegi, N., Hültner, L., Hoppe, P. S., Schroeder, T., Vandenabeele, P., Bornkamm, G. W., & Greten, F. R. (2016) · Blood · doi:10.1182/blood-2015-06-654194 · Cited by 247
“Cell death observed in the absence of caspase 8 is inhibited upon the additional deletion of Rip3, suggesting that caspase 8 inhibits RIP3-mediated necroptosis.(24,25,29) For personal use only.”
BackgroundIntracellular regulation of TNF activity in health and disease
Varfolomeev, E. E., & Vucic, D. (2016) · Cytokine · doi:10.1016/j.cyto.2016.08.035 · Cited by 257
RIP kinases as modulators of inflammation and immunity
He, S., & Wang, X. (2018) · Nature Immunology · doi:10.1038/s41590-018-0188-x · Cited by 250
ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation
de Reuver, R., Verdonck, S., Dierick, E., Nemegeer, J., Hessmann, E., Ahmad, S., Jans, M., Blancke, G., Nieuwerburgh, F. V., Botzki, A., et al. (2022) · Nature · doi:10.1038/s41586-022-04974-w · Cited by 253
Moriwaki, K., Bertin, J., Gough, P. J., Orlowski, G. M., & Chan, F. K. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.16 · Cited by 251
RIP kinases: key decision makers in cell death and innate immunity
Humphries, F., Yang, S., Wang, B., & Moynagh, P. N. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.126 · Cited by 249
Alvarez-Diaz, S., Dillon, C. P., Lalaoui, N., Tanzer, M. C., Rodriguez, D. A., Lin, A., Lebois, M., Hakem, R., Josefsson, E. C., O’Reilly, L. A., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.016 · Cited by 242
“…Ripk3 / mutant mice) accumulate large numbers of DN T cells that are thought to be descendants of previously activated CD3+CD4 CD8+ T cells that have failed to undergo programmed cell death (Dillon et al., 2012; Kaiser et al., 2011; O’Reilly et al., 2009; Oberst et al., 2011; Siegel et al., 2000).”
BackgroundInfluentialSelf-citationMan, S. M., Tourlomousis, P., Hopkins, L., Monie, T. P., Fitzgerald, K. A., & Bryant, C. E. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301581 · Cited by 239
“Caspase-82/2 ripk32/2 BMMs were used because genetic ablation of caspase-8 in mice results in embryonic lethality, which can be rescued by ablation of RIPK3 (35, 36).”
MethodInfluentialDeath Receptor-Ligand Systems in Cancer, Cell Death, and InflammationPreprint
Walczak, H. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008698 · Cited by 250
“Recently, however, a plausible explanation was offered: Concomitant deletion of RIP3 or RIP1 rescued mice deficient for caspase-8 or FADD from embryonic lethality (Kaiser et al. 2011; Oberst et al. 2011; Zhang et al. 2011).”
BackgroundGuidelines for evaluating myocardial cell death
Mishra, P. K., Adameová, A., Hill, J. A., Baines, C. P., Kang, P. M., Downey, J. M., Narula, J., Takahashi, M., Abbate, A., Piristine, H. C., et al. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00259.2019 · Cited by 246
“In contrast, the insufficiently active caspase-8 or its genetic and pharmacological inhibition (106, 193) prevents RIP1 cleavage, thereby promoting its association with RIP3 to form an amyloid-like protein complex known as the necrosome (259).”
BackgroundBanoth, B., Tuladhar, S., Karki, R., Sharma, B. R., Briard, B., Kesavardhana, S., Burton, A., & Kanneganti, T.-D. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015924 · Cited by 237
“WT, Zbp1 (21, 41), Zbp1 (20), Casp1/11 (42), Gsdmd (43), Asc (44), Mlkl (45), Ripk3 (46), Ripk3Casp8 (47), and Casp1/11Ripk3Casp8 (18) mice have been described previously.”
Demarco, B., Grayczyk, J. P., Bjånes, E., Roy, D. L., Tonnus, W., Assenmacher, C., Radaelli, E., Fettrelet, T., Mack, V., Linkermann, A., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc3465 · Cited by 238
Vince, J. E., Nardo, D. D., Gao, W., Vince, A. J., Hall, C. M., McArthur, K., Simpson, D. S., Vijayaraj, S. L., Lindqvist, L., Bouillet, P., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.103 · Cited by 236
“As caspase-8 deficiency in mice is embryonic lethal because of unrestrained necroptotic cell death (Kaiser et al., 2011; Oberst et al., 2011), we examined BAX/BAK signaling in mice lacking necroptotic receptor interacting protein kinase-3 (RIPK3) and caspase-8 ubiquitously (Ripk3 / Caspase-8 / ) or specifically in mye…”
BackgroundThe Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 236
Zirngibl, M., Assinck, P., Sizov, A., Caprariello, A. V., & Plemel, J. R. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00538-8 · Cited by 233
Vanlangenakker, N., Bertrand, M. J. M., Bogaert, P., Vandenabeele, P., & Berghe, T. V. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.111 · Cited by 236
“However, the use of the FRET-based apoptosis sensor revealed that the L929p Casper3-BG cells depleted of c-FLIP still died in a caspaseindependent way when exposed to TNF (Supplementary Figures 4a and b), thereby confirming the study of Oberst et al. 17 showing that in L929 cells, c-FLIP silencing promotes zVAD-fmk-in…”
InfluentialAn Inflammatory Perspective on Necroptosis
Kearney, C. J., & Martin, S. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.02.024 · Cited by 232
NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation
Sundaram, B., Nagakannan, P., Kim, H. J., Abdelaal, H. M., Mall, R., Indari, O., Sarkar, R., Tweedell, R. E., Alonzo, E. Q., Klein, J. D., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.034 · Cited by 238
Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling
Antonopoulos, C. H., Russo, H. M., Sanadi, C. E. E., Martin, B. N., Li, X., Kaiser, W. J., Mocarski, E. S., & Dubyak, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.652321 · Cited by 232
“Caspase-8knock-out mice are embryonic lethal due to unrestrained necroptosis and require co-deletion of RIP3 to rescue viability (7, 36).”
BackgroundTNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer
Walczak, H. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01066.x · Cited by 233
“However, a complex consisting of FADD, caspase-8, and cFLIP counteracts regulated necrosis (109, 138, 139) by the protease activity of the caspase-8-cFLIP heteromer (138).”
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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