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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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Items 201–300 of 999
RIPK1 Distinctly Regulates Yersinia-Induced Inflammatory Cell Death, PANoptosis
Malireddi, R. K. S., Kesavardhana, S., Karki, R., Kancharana, B., Burton, A. R., & Kanneganti, T.-D. (2020) · ImmunoHorizons · doi:10.4049/immunohorizons.2000097 · Cited by 224
“Casp1/11−/− (38), Ripk1−/− (39); Ripk3−⁄− (40); Ripk3−⁄−Casp8−⁄− (41), Ripk3−⁄−Casp8−⁄−Casp1/11−⁄− (8) Zbp1−⁄− (42), Casp3–/– (43), Casp7–/– (44), Gsdmd–/– (45), and Mlkl–/– (46), mouse strains were all described previously.”
ADAR1 mutation causes ZBP1-dependent immunopathology
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The ‘complexities’ of life and death: Death receptor signalling platforms
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“who demonstrated that it occurs via formation of an ‘inhibitory’ caspase-8-FLIPL heterodimer [48].”
BackgroundOrigin and Consequences of Necroinflammation
Sarhan, M., Land, W. G., Tonnus, W., Hugo, C., & Linkermann, A. (2018) · Physiological Reviews · doi:10.1152/physrev.00041.2016 · Cited by 217
LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis
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Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK
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“Experimental procedures Mice Nlrp3−/− (83), Casp11−/− (84), Gsdmd–/– (85), Gsdme–/– (86), Mlkl–/– (87), Asc–/– (88), Nlrc4−/− (89), Aim2−/− (90), Ripk3–/– (91), Casp8–/–Ripk3–/– (92), Casp8–/–Ripk3–/–Casp1/11–/– (35), and MyD88–/– (93) mice have been described previously.”
Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss
Maremonti, F., Meyer, C., & Linkermann, A. (2022) · Journal of the American Society of Nephrology · doi:10.1681/asn.2021101293 · Cited by 213
RIPK3-Mediated Necroptosis Promotes Donor Kidney Inflammatory Injury and Reduces Allograft Survival
Lau, A. N., Wang, S., Jiang, J., Haig, A. R., Pavlosky, A., Linkermann, A., Zhang, Z.-X., & Jevnikar, A. M. (2013) · American Journal of Transplantation · doi:10.1111/ajt.12447 · Cited by 204
“However, recent studies using TNF-a indicate that a primary function of caspase-8 may be also to block necroptosis (22,23,30).”
BackgroundMolecular crosstalk between apoptosis, necroptosis, and survival signaling
Berghe, T. V., Kaiser, W. J., Bertrand, M. J. M., & Vandenabeele, P. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723556.2014.975093 · Cited by 209
Remick, B. C., Gaidt, M. M., & Vance, R. E. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-031732 · Cited by 218
Control of Life-or-Death Decisions by RIP1 Kinase
Christofferson, D. E., Li, Y., & Yuan, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170259 · Cited by 203
Rauf, A., Khalil, A. A., Awadallah, S. M., Khan, S. A., Abu‐Izneid, T., Kamran, M., Hemeg, H. A., Mubarak, M. S., Khalid, A., & Wilairatana, P. (2023) · Food Science & Nutrition · doi:10.1002/fsn3.3784 · Cited by 220
“Because of its high expression, RIP3, a protein kinase, triggers cellular death in numerous cell lines (Oberst et al., 2011 ).”
BackgroundFatty acid-related modulations of membrane fluidity in cells: detection and implications
Maulucci, G., Cohen, O., Daniel, B., Sansone, A., Πετροπούλου, Π.-Ι., Filou, S., Spyridonidis, A., Pani, G., Spirito, M. D., Chatgilialoglu, C., et al. (2016) · Free Radical Research · doi:10.1080/10715762.2016.1231403 · Cited by 203
“Aside from the complexity of chemically analyzing numerous molecules [14], the extraction of correlations to meaningful biological interactions is not trivial, because lipids may exhibit diverse functions in different cell types, that greatly enhance inter-individual variability [15].”
BackgroundMcComb, S., Cessford, E., Alturki, N. A., Joseph, J., Shutinoski, B., Startek, J. B., Gamero, A. M., Mossman, K. L., & Sad, S. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1407068111 · Cited by 190
“This result adds to previous work showing that caspase-8 promotes the regulation of the Rip1/Rip3 necrosome (36, 37).”
ResultGut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer
Xie, Y., Zhao, Y., Shi, L., Li, W., Chen, K., Li, M., Chen, X., Zhang, H., Li, T., Matsuzawa, Y., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133264 · Cited by 202
Multiple roles of caspase-8 in cell death, inflammation, and innate immunity
Ørning, P., & Lien, E. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0420-305r · Cited by 206
The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia
Zheng, Z., Deng, W., Bai, Y., Miao, R., Mei, S., Zhang, Z., Pan, Y., Wang, Y., Min, R., Deng, F., et al. (2021) · Science · doi:10.1126/science.abg0269 · Cited by 199
IAPs limit activation of RIP kinases by TNF receptor 1 during development
Moulin, M., Anderton, H., Voss, A. K., Thomas, T., Wong, W. W., Bankovacki, A., Feltham, R., Chau, D., Cook, W. D., Silke, J., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.18 · Cited by 193
“…of Fadd null embryos to birth (Zhang et al , 2011), and deletion of RIPK3, which is thought to act downstream of RIPK1 in the necroptotic pathway, was shown to allow Casp8 KO mice to develop into normal, fertile adults (Ch’en et al , 2011; Kaiser et al , 2011; Oberst et al , 2011) (Figure 8A).”
Murakami, Y., Matsumoto, H., Roh, M., Giani, A., Kataoka, K., Morizane, Y., Kayama, M., Thanos, A., Nakatake, S., Notomi, S., et al. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.109 · Cited by 199
Flipping the dogma – phosphatidylserine in non-apoptotic cell death
Shlomovitz, I., Speir, M., & Gerlic, M. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0437-0 · Cited by 189
Necroptosis in Immunity and Ischemia-Reperfusion Injury
Linkermann, A., Hackl, M. J., Kunzendorf, U., Walczak, H., Krautwald, S., & Jevnikar, A. M. (2013) · American Journal of Transplantation · doi:10.1111/ajt.12448 · Cited by 193
“5 of embryonic development, is completely reversedwith the additional deletion of RIPK3 (7,8).”
BackgroundRoles of RIPK3 in necroptosis, cell signaling, and disease
Morgan, M. J., & Kim, Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00868-z · Cited by 197
Peter, M. E. (2011) · Nature · doi:10.1038/471310a · Cited by 191
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 188
“RIPK1 as a Master Regulator of Cell Death Genetic studies in mice deficient for key components of the apoptosis machinery provided the first insights on the mechanisms that regulate RIPK1/RIPK3-dependent necroptosis [22–25] (Table 1 and Figure 2, Key Figure).”
BackgroundInfluentialBrumatti, G., Ma, C., Lalaoui, N., Nguyen, N.-Y. N., Navarro, M., Tanzer, M. C., Richmond, J., Ghisi, M., Salmon, J. M., Silke, N., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad3099 · Cited by 190
“The caspase-8/cFLIPL heterodimer is catalytically active and has been proposed to be the form of caspase-8 that inhibits necroptosis (33, 34).”
BackgroundSelf-citationThe essentials of developmental apoptosis
Voss, A. K., & Strasser, A. (2020) · F1000Research · doi:10.12688/f1000research.21571.1 · Cited by 185
Necroptosis: an alternative cell death program defending against cancer
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CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3
Seo, J., Lee, E.-W., Sung, H., Seong, D., Dondelinger, Y., Shin, J., Jeong, M., Lee, H.-K., Kim, J.-H., Han, S. Y., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3314 · Cited by 182
Novel Roles for Caspase-8 in IL-1β and Inflammasome Regulation
Gurung, P., & Kanneganti, T. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.08.025 · Cited by 185
The molecular relationships between apoptosis, autophagy and necroptosis
Lalaoui, N., Lindqvist, L., Sandow, J. J., & Ekert, P. G. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.02.003 · Cited by 181
“This heterodimer of cFLIPL and caspase-8 functions to block necroptosis, by inhibiting RIPK3 [97].”
BackgroundPUMA amplifies necroptosis signaling by activating cytosolic DNA sensors
Chen, D., Tong, J., Yang, L., Liang, W., Stolz, D. B., Yu, J., Zhang, J., & Zhang, L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717190115 · Cited by 191
Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation
Kim, E. H., Wong, S., & Martinez, J. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0179-3 · Cited by 181
Poly-ubiquitination in TNFR1-mediated necroptosis
Dondelinger, Y., Darding, M., Bertrand, M. J. M., & Walczak, H. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2191-4 · Cited by 173
“Indeed, necroptosis only occurs when caspase-8 activation fails or is inhibited, indicating that caspase-8-mediated apoptosis actively represses necroptosis [51–55].”
BackgroundNecroptotic cell death in anti‐cancer therapy
Krysko, O., Aaes, T. L., Kagan, V. E., D'Herde, K. G. M. A., Bachert, C., Leybaert, L., Vandenabeele, P., & Krysko, D. V. (2017) · Immunological Reviews · doi:10.1111/imr.12583 · Cited by 180
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FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP
Tsuchiya, Y., Nakabayashi, O., & Nakano, H. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161226232 · Cited by 174
“[131] reported that the embryonic lethal phenotype of Casp8-deficent mice was rescued by the additional deletion of Ripk3, a central player of necroptosis, although these mice displayed a progressive lympho-accumulative disease.”
BackgroundCitrobacter rodentium–host–microbiota interactions: immunity, bioenergetics and metabolism
Mullineaux-Sanders, C., Sanchez‐Garrido, J., Hopkins, E. G. D., Shenoy, A. R., Barry, R. E., & Frankel, G. M. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0252-z · Cited by 180
RIPK-Dependent Necrosis and Its Regulation by Caspases: A Mystery in Five Acts
Green, D. R., Oberst, A., Dillon, C. P., Weinlich, R., & Salvesen, G. S. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.09.003 · Cited by 175
“…et al., 2011), and (2) the pox virus serpin CrmA prevents caspase-8-dependent apoptosis in T lymphocytes (Smith et al., 1996) and fibroblasts (Oberst et al., 2011) without promoting necrosis; CrmA preferentially inhibits caspase-8 homodimers over caspase-8-FLIP activity (Oberst et al., 2011).”
BackgroundInfluentialSelf-citationThe intersection of cell death and inflammasome activation
Vince, J. E., & Silke, J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2205-2 · Cited by 180
Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy
Rosenbaum, S. R., Wilski, N. A., & Aplin, A. E. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0805 · Cited by 177
Inhibiting the inhibitors: Targeting anti-apoptotic proteins in cancer and therapy resistance
Shahar, N., & Larisch, S. (2020) · Drug Resistance Updates · doi:10.1016/j.drup.2020.100712 · Cited by 175
Absence of RIPK3 predicts necroptosis resistance in malignant melanoma
Geserick, P., Wang, J., Schilling, R., Horn, S., Harris, P. A., Bertin, J., Gough, P. J., Feoktistova, M., & Leverkus, M. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.240 · Cited by 172
An evolutionary perspective on the necroptotic pathway
Dondelinger, Y., Hulpiau, P., Saeys, Y., Bertrand, M. J. M., & Vandenabeele, P. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.06.004 · Cited by 159
Necrosome core machinery: MLKL
Zhang, J., Yu, Y., He, W., & Sun, L. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2190-5 · Cited by 166
“Mice with deletions of any of the complex-IIB genes display severe embryonic developmental defects that lead to either embryonic (Casp8; Fadd; cFlip) or postnatal lethality (Rip1) [19, 20].”
BackgroundCaspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis
Tummers, B., Mari, L., Guy, C. S., Heckmann, B. L., Rodríguez, D. A., Rühl, S., Moretti, J., Crawford, J. C., Fitzgerald, P., Kanneganti, T., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.010 · Cited by 166
“However, both Casp8DA/DA and Casp8DA/DAMlkl−/− animals succumbed more rapidly than WT or Mlkl−/− mice upon high-dose LPS injection, whereas Casp8−/− Mlkl−/− mice were protected (Figure 3D), as previously described for Casp8−/−Ripk3−/− mice (Kaiser et al., 2011; Mandal et al., 2018).”
BackgroundInfluentialSelf-citationTezel, G. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100998 · Cited by 175
“By interacting with caspase-8, this inactive caspase-8 homolog functions as a molecular switch between cell death, survival, and inflammation signals after TNFR or TLR binding (Chang et al., 2002; Irmler et al., 1997; Oberst et al., 2011; Silke and Strasser, 2013; Vandenabeele and Melino, 2012).”
BackgroundVandenabeele, P., Grootjans, S., Callewaert, N., & Takahashi, N. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.151 · Cited by 166
Erental, A., Sharon, I., & Engelberg–Kulka, H. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001281 · Cited by 165
“Recent publications [45–48] provide evidence that in eukaryotes, the two PCD pathways, apoptosis and necrosis, are intertwined.”
BackgroundLee, E., Song, C.-H., Bae, S.-J., Ha, K.-T., & Karki, R. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01069-y · Cited by 164
RIPK3 as a potential therapeutic target for Gaucher's disease
Vitner, E. B., Salomon, R., Farfel‐Becker, T., Meshcheriakova, A., Ali, M., Klein, A. D., Platt, F. M., Cox, T. M., & Futerman, A. H. (2014) · Nature Medicine · doi:10.1038/nm.3449 · Cited by 165
Cell Death in the Developing Brain after Hypoxia-Ischemia
Thornton, C., Leaw, B., Mallard, C. E., Nair, S., Jinnai, M., & Hagberg, H. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00248 · Cited by 166
“Caspase-8 actively inhibits necroptosis through degradation of RIP1 and RIP3 (Lin et al., 1999; Oberst et al., 2011) but in the absence of caspase-8, viral or genetic inhibition (Cho et al., 2009; Kaiser et al., 2011) or high RIP3 expression (Zhang et al., 2009), necroptosis will occur.”
BackgroundNecroptosis, in vivo detection in experimental disease models
Jouan-Lanhouet, S., Riquet, F. B., Duprez, L., Berghe, T. V., Takahashi, N., & Vandenabeele, P. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.08.010 · Cited by 166
“Necrosome formation is negatively regulated by many proteins [6, 7], including FADD, caspase-8, FLIPL, A20, the linear ubiquitin chain assembly complex, TAK1, and cellular Page 9 of 42 Ac ce pt ed M an us cr ip t 9 inhibitor of apoptosis proteins (cIAPs) [11-13, 56, 57].”
BackgroundInfluentialKilling a cancer: what are the alternatives?
Kreuzaler, P. A., & Watson, C. J. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3264 · Cited by 164
Sawai, H., & Domae, N. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.186 · Cited by 161
Apoptotic Caspases: Multiple or Mistaken Identities?
McArthur, K., & Kile, B. T. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.003 · Cited by 166
Rodrigue‐Gervais, I. G., Labbè, K., Dagenais, M., Dupaul-Chicoine, J., Champagne, C., Morizot, A., Skeldon, A. M., Brincks, E. L., Vidal, S. M., Griffith, T. S., et al. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2013.12.003 · Cited by 161
Günther, C., He, G.-W., Kremer, A. E., Murphy, J. M., Petrie, E. J., Amann, K., Vandenabeele, P., Linkermann, A., Poremba, C., Schleicher, U., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87545 · Cited by 157
Wong, W. W.-L., Vince, J. E., Lalaoui, N., Lawlor, K. E., Chau, D., Bankovacki, A., Anderton, H., Metcalf, D., O’Reilly, L. A., Jost, P. J., et al. (2014) · Blood · doi:10.1182/blood-2013-06-510743 · Cited by 159
“In most cellular systems, the RIPK1 inhibitor Nec-1 only blocks death receptor– induced (eg, TNFR1) cell death when it is combined with caspase inhibitors.(22,24,35,37,38) It was therefore surprising that Nec-1 alone completelypreventedSmacmimetic killingofBMDMsover a rangeof 5-50mM(Figure 5Aanddatanot shown).”
BackgroundIt cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival
Oberst, A., & Green, D. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3214 · Cited by 160
Self-citationInnate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease
Chen, W., Gullett, J. M., Tweedell, R. E., & Kanneganti, T. (2023) · European Journal of Immunology · doi:10.1002/eji.202250235 · Cited by 161
Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis
Weinlich, R., Oberst, A., Dillon, C. P., Janke, L. J., Milasta, S., Lukens, J. R., Rodriguez, D. A., Gurung, P., Savage, C., Kanneganti, T. D., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.045 · Cited by 157
“Embryonic lethality in caspase-8−/− mice can be fully rescued by ablation of RIPK3 (Kaiser et al., 2011; Oberst et al., 2011); therefore four genotypes were examined: CreER−, casp8f/f, ripk3+/+; CreER−, casp8f/f, ripk3−/−; CreER+, casp8f/f, ripk3+/+ and CreER+, casp8f/f, ripk3−/−.”
BackgroundMethodInfluentialSelf-citationT cell–intrinsic ASC critically promotes TH17-mediated experimental autoimmune encephalomyelitis
Martin, B. N., Wang, C., Zhang, C.-J., Kang, Z., Gulen, M. F., Zepp, J. A., Zhao, J., Bian, G., Do, J., Min, B., et al. (2016) · Nature Immunology · doi:10.1038/ni.3389 · Cited by 159
Shenderov, K., Riteau, N., Yip, R. H. N., Mayer-Barber, K. D., Oland, S., Hieny, S. E., Fitzgerald, P., Oberst, A., Dillon, C. P., Green, D. R., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302549 · Cited by 156
“Therefore, to investigate the role of caspase-8 in IL-1b maturation in response to ER stress and LPS, we used BMDMs from Ripk3 Casp8, Ripk3 Casp8, and Ripk3 Casp8 mice (13).”
MethodSelf-citationStaying Alive: Cell Death in Antiviral Immunity
Upton, J. W., & Chan, F. K.-M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.01.027 · Cited by 160
“FADD- and caspase-8-mediated inhibition of necrosis tampers damaging necrotic cell death during embryonic development (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011).”
BackgroundAutophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition
Bray, K., Mathew, R., Lau, A., Kamphorst, J. J., Fan, J., Chen, J., Chen, H.-Y., Ghavami, A., Stein, M. N., DiPaola, R. S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041831 · Cited by 159
“Necroptosis is a specialized form of programmed necrosis that must be inactivated to prevent embryonic lethality [60,61,62].”
BackgroundRIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
Chen, H., Fang, Y., Wu, J., Chen, H., Zou, Z., Zhang, X., Shao, J., & Xu, Y. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0936-8 · Cited by 155
RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review)
Liu, Y., Liu, T., Lei, T., Zhang, D., Du, S., Girani, L., Qi, D., Chen, L., Tong, R., & Wang, Y. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4244 · Cited by 157
MLKL: Functions beyond serving as the Executioner of Necroptosis
Zhan, C., Huang, M., Yang, X., & Hou, J. L. (2021) · Theranostics · doi:10.7150/thno.54072 · Cited by 155
“Because apoptosis is indispensable for mammalian development [7, 8], apoptosis is not an ideal target for controlling inflammation.”
BackgroundDesai, B. N., Krapivinsky, G. B., Navarro, B., Krapivinsky, L., Carter, B. C., Febvay, S., Delling, M., Penumaka, A., Ramsey, I. S., Manasian, Y., et al. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.04.006 · Cited by 151
“In contrast, caspase-8 substrates like Bid (Li et al., 1998) and RIPK3 (Kaiser et al., 2011; Oberst et al., 2011) are thought to be cleaved selectively by caspase-8 during extrinsic apoptosis.”
BackgroundProgrammed necrosis and necroptosis signalling
Feoktistova, M., & Leverkus, M. (2014) · FEBS Journal · doi:10.1111/febs.13120 · Cited by 159
Viral modulation of programmed necrosis
Kaiser, W. J., Upton, J. W., & Mocarski, E. S. (2013) · Current Opinion in Virology · doi:10.1016/j.coviro.2013.05.019 · Cited by 151
“Importantly, embryonic lethality due to germ line Casp8 deficiency in mice depends on RIP1 and RIP3 [63,90,92] and is not influenced by germ line elimination of the other RHIM-dependent interaction partners, DNA-dependent activator of IRFs (DAI) [93] or TIR-domain-containing adapter-inducing IFN β (TRIF) [94].”
BackgroundcIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation
McComb, S., Cheung, H. H., Korneluk, R. G., Wang, S., Krishnan, L., & Sad, S. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2012.59 · Cited by 148
Inflammatory Caspases: Toward a Unified Model for Caspase Activation by Inflammasomes
Ross, C. M., Chan, A. H., von Pein, J. B., Maddugoda, M. P., Boucher, D., & Schroder, K. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-030653 · Cited by 157
Doerflinger, M., Deng, Y., Whitney, P. G., Salvamoser, R., Engel, S., Kueh, A. J., Tai, L., Bachem, A., Gressier, E., Geoghegan, N. D., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.07.004 · Cited by 147
“, 2013),Casp8;Ripk3 (Oberst et al., 2011),Casp1;Casp11 (Kuida et al.”
BackgroundMethodHarnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries
Montinaro, A., & Walczak, H. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01059-z · Cited by 154
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes
Bebber, C. M., Thomas, E. S., Stroh, J., Chen, Z., Androulidaki, A., Schmitt, A., Höhne, M. N., Stüker, L., Alves, C. D. P., Khonsari, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22336-4 · Cited by 144
“Downregulation of caspase 8, can enable unrestricted activation of the necroptosis pathway through relieving caspase 8-imposed negative regulation RIPK1 and 3 (11, 33) (Figure 1B).”
Viruses and the Diversity of Cell Death
Danthi, P. (2016) · Annual Review of Virology · doi:10.1146/annurev-virology-110615-042435 · Cited by 144
Linear ubiquitination in immunity
Shimizu, Y., Taraborrelli, L., & Walczak, H. (2015) · Immunological Reviews · doi:10.1111/imr.12309 · Cited by 139
“Interestingly, their cleavage by the caspase-8/c-FLIP heterodimer, which does not induce apoptosis, appears to be required to block necroptosis (25, 26).”
BackgroundSuppression of RIP3-dependent Necroptosis by Human Cytomegalovirus
Omoto, S., Guo, H., Talekar, G. R., Roback, L., Kaiser, W. J., & Mocarski, E. S. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.646042 · Cited by 145
Nonapoptotic cell death in acute kidney injury and transplantation
Linkermann, A. (2016) · Kidney International · doi:10.1016/j.kint.2015.10.008 · Cited by 141
Recent Insights on Inflammasomes, Gasdermin Pores, and PyroptosisPreprint
de Vasconcelos, N. M., & Lamkanfi, M. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036392 · Cited by 139
“Co-ablation of either ASC or caspase-8 (in RIPK3 knockout animals to prevent caspase-8-driven embryonic lethality [Kaiser et al. 2011; Oberst et al. 2011]) in the caspase-1/-11-deficient background phenocopies NLRC4 deletion on flagellin challenge in vivo or infection with Legionella spp.…”
BackgroundTLR activation regulates damage‐associated molecular pattern isoforms released during pyroptosis
Nyström, S., Antoine, D. J., Lundbäck, P., Lock, J. G., Niță, A. F., Högstrand, K., Grandien, A., Erlandsson-Harris, H., Andersson, U., & Applequist, S. E. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.328 · Cited by 138
“However, caspase-8 can be specifically inhibited by FLIP-short (cFLIP S ) and FLIP-long (cFLIP L ) (Weinlich et al , 2011).”
The roles of FADD in extrinsic apoptosis and necroptosis
Lee, E., Seo, J.-H., Jeong, M.-H., Lee, S.-S., & Song, J.-W. (2012) · BMB Reports · doi:10.5483/bmbrep.2012.45.9.186 · Cited by 137
“5, despite the absence of apoptosis (119, 137).”
Endothelial cell apoptosis in angiogenesis and vessel regression
Watson, E. L., Grant, Z. L., & Coultas, L. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2577-y · Cited by 146
Cell death checkpoints in the TNF pathway
Huyghe, J., Priem, D., & Bertrand, M. J. M. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.05.007 · Cited by 147
ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages
Lee, B. L., Mirrashidi, K. M., Stowe, I. B., Kummerfeld, S., Watanabe, C. K., Haley, B., Cuellar, T. L., Reichelt, M., & Kayagaki, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-21998-3 · Cited by 141
Sublethal necroptosis signaling promotes inflammation and liver cancer
Vucur, M., Ghallab, A., Schneider, A. T., Adili, A., Cheng, M., Castoldi, M., Singer, M. T., Büttner, V., Keysberg, L. S., Küsgens, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.05.017 · Cited by 142
Dichotomy between RIP1- and RIP3-Mediated Necroptosis in Tumor Necrosis Factor-α-Induced Shock
Linkermann, A., Bräsen, J. H., Zen, F. D., Weinlich, R., Schwendener, R. A., Green, D. R., Kunzendorf, U., & Krautwald, S. (2012) · Molecular Medicine · doi:10.2119/molmed.2011.00423 · Cited by 138
Self-citationTumour necrosis factor in infectious disease
Waters, J. P., Pober, J. S., & Bradley, J. R. (2013) · The Journal of Pathology · doi:10.1002/path.4187 · Cited by 136
Kearney, C. J., Cullen, S. P., Tynan, G. A., Henry, C. M., Clancy, D. M., Lavelle, E. C., & Martin, S. J. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2014.222 · Cited by 135
Functions of caspase 8: The identified and the mysterious
Salvesen, G. S., & Walsh, C. M. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.03.005 · Cited by 141
“This is supported by studies demonstrating that cFLIP binding promotes casp8 activation without interdomain cleavage [50], and that FLIPL prevents necroptosis [114, 122].”
BackgroundSelf-citationNanomaterials Toxicity and Cell Death Modalities
Stefano, D. D., Carnuccio, R., & Maiuri, M. C. (2012) · Journal of Drug Delivery · doi:10.1155/2012/167896 · Cited by 140
NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis
Gurung, P., Burton, A. R., & Kanneganti, T. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1601636113 · Cited by 133
“Nlrp3 (27), Casp1 (27), Il1b (28), Il1r (29), Ripk3Casp8 (30), Ctsb (31), Ctsc (32), Ctsg (33), and Tnfr (34) mice have been previously described.”
The mechanism of necroptosis in normal and cancer cells
Fulda, S. (2013) · Cancer Biology & Therapy · doi:10.4161/cbt.26428 · Cited by 134
The Two Faces of Receptor Interacting Protein Kinase-1
Weinlich, R., & Green, D. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.11.001 · Cited by 132
“ble-deficient animals develop normally and mature (Dillon et al., 2012; Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundInfluentialSelf-citationInsights on the crosstalk among different cell death mechanisms
Eskander, G., AbdelHamid, S. G., Wahdan, S. A., & Radwan, S. M. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02328-9 · Cited by 150
Lee, E., Kim, J.-H., Ahn, Y.-H., Seo, J., Ko, A., Jeong, M., Kim, S.-J., Ro, J. Y., Park, K.-M., Lee, H., et al. (2012) · Nature Communications · doi:10.1038/ncomms1981 · Cited by 130
An outline of necrosome triggers
Berghe, T. V., Hassannia, B., & Vandenabeele, P. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2189-y · Cited by 134
“This concept was first proposed based on studies of DR signaling in fibrosarcoma cells [28, 29], and later confirmed in vivo by the rescue of the embryonal lethality of CASP8 or FADD deficiency by RIPK3 depletion [9, 14, 16].”
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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