Survival Function of the FADD-CASPASE-8-cFLIPL Complex
Open accessAbstract
Caspase-8, the initiator caspase of the death receptor pathway of apoptosis, its adapter molecule, FADD, required for caspase-8 activation, and cFLIPL, a caspase-8-like protein that lacks a catalytic site and blocks caspase-8-mediated apoptosis, are each essential for embryonic development. Animals deficient in any of these genes present with E10.5 embryonic lethality. Recent studies have shown that development in caspase-8-deficient mice is rescued by ablation of RIPK3, a kinase that promotes a form of programmed, necrotic cell death. Here, we show that FADD, RIPK3 double-knockout mice develop normally but that the lethal effects of cFLIP deletion are not rescued by RIPK3 deficiency. Remarkably, in mice lacking FADD, cFLIP, and RIPK3, embryonic development is normal. This can be explained by the convergence of two cell processes: the enzymatic activity of the FADD-caspase-8-cFLIPL complex blocks RIPK3-dependent signaling (including necrosis), whereas cFLIPL blocks RIPK3-independent apoptosis promoted by the FADD-caspase-8 complex.
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Cflar−/− mice require concomitant knockout of Ripk3 and Fadd to develop into adulthood, underscoring inhibitory role of c-FLIP in both necroptosis and extrinsic apoptosis.
“Of note, Cflar−/− mice require the concomitant knockout of Ripk3 and Fadd to develop into adulthood, which underscores the inhibitory role of c-FLIP in both necroptosis and extrinsic apoptosis reported above [483, 486].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [486]
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Kang, T., Ben-Moshe, T., Varfolomeev, E., Pewzner‐Jung, Y., Yogev, N., Jurewicz, A., Waisman, A., Brenner, O., Haffner, R., Gustafsson, E., et al. (2004) · Journal of Immunology · doi:10.4049/jimmunol.173.5.2976 · Cited by 425 · cited 5× · see citing works
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“Immunoprecipitation of DISC-associated complexes was carried out using buffer and lysis conditions previously described (Geserick et al., 2009).”
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BackgroundIt cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival
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“Further, because FADD, RIPK1 (Zhang et al., 2011) and FADD, RIPK3 (Figure 1) DKO mice develop normally in utero, both RIPK1 and RIPK3 mediate embryonic lethality, most likely by the process of RIPK1RIPK3-mediated programmed necrosis (Weinlich et al., 2011).”
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“If so, why is the system “built” in this complex manner? One possibility relates to the dissemination of DNA viruses, which often carry endogenous inhibitors of caspase-8 (Weinlich et al., 2011).”
BackgroundInfluentialSelf-citation
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“…/ (cid:1) (survive to adulthood) [110,111] Mlkl (cid:1) / (cid:1) Casp1 (cid:1) / (cid:1) (survive to adulthood) [110,111] Cardiac failure and abdominal hemorrhage [168] Ripk1 (cid:1) / (cid:1) (postnatal lethality) [169] Ripk3 (cid:1) / (cid:1) (survive but develop ALPS) [170] FLIP Embryonic (E10.”
The diverse role of RIP kinases in necroptosis and inflammation
Silke, J., Rickard, J. A., & Gerlic, M. (2015) · Nature Immunology · doi:10.1038/ni.3206 · Cited by 522 · see citing works
Necroptosis in health and diseases
Zhou, W., & Yuan, J. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.07.013 · Cited by 414 · see citing works
“efects are rescued by double knockout of FADD and RIP3 but not IP3 knockout alone, suggesting that cFLIP is a suppressor of both poptosis and necroptosis [81].”
BackgroundNewton, K., & Manning, G. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014830 · Cited by 401 · see citing works
Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis
Rodríguez, D. A., Weinlich, R., Brown, S., Guy, C. S., Fitzgerald, P., Dillon, C. P., Oberst, A., Quarato, G., Low, J. A., Cripps, J. G., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.70 · Cited by 379 · see citing works
Self-citationMalireddi, R. K. S., Gurung, P., Kesavardhana, S., Samir, P., Burton, A. R., Mummareddy, H., Vogel, P., Pelletier, S. W., Burgula, S., & Kanneganti, T. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20191644 · Cited by 386 · see citing works
Die another way – non-apoptotic mechanisms of cell death
Tait, S. W. G., Ichim, G., & Green, D. R. (2014) · Journal of Cell Science · doi:10.1242/jcs.093575 · Cited by 366 · see citing works
“In vivo support of this model comes from the finding that embryonic lethality caused by caspase-8 or FADD loss in vivo can be completely rescued by RIPK3 ablation (Dillon et al., 2012; Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundSelf-citationRIPK1 and RIPK3: critical regulators of inflammation and cell death
Newton, K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.01.001 · Cited by 367 · see citing works
Apoptotic cell death in disease—Current understanding of the NCCD 2023
Vitale, I., Pietrocola, F., Guilbaud, E., Aaronson, S. A., Abrams, J., Adam, D., Agostini, M., Agostinis, P., Alnemri, E. S., Altucci, L., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01153-w · Cited by 359 · see citing works
Self-citationInterferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases
Thapa, R. J., Nogusa, S., Chen, P., Maki, J. L., Lerro, A., Andrake, M., Rall, G. F., Degterev, A., & Balachandran, S. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301218110 · Cited by 355 · see citing works
“By contrast, a parallel intercross using fadd mice on a ripk3 background produced fadd pups at roughly Mendelian frequency [9 of 40 live births, in agreement with a previous report (16)], indicating that IFN signaling is likely not the trigger for the premature RIP kinasedependent death of fadd embryos (Fig.”
ResultRIP3: a molecular switch for necrosis and inflammationPreprint
Moriwaki, K., & Chan, F. K.-M. (2013) · Genes & Development · doi:10.1101/gad.223321.113 · Cited by 353 · see citing works
“Consistent with this proposition, RIP3/FADD double deficiency rescued the lethality of cFLIP / mice (Dillon et al. 2012).”
BackgroundCaspases Connect Cell-Death Signaling to Organismal Homeostasis
Galluzzi, L., López-Soto, A., Kumar, S., & Kroemer, G. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.020 · Cited by 350 · see citing works
Programmed Necrosis in the Cross Talk of Cell Death and Inflammation
Chan, F. K.-M., Luz, N. F., & Moriwaki, K. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112248 · Cited by 350 · see citing works
“Because Fadd−/−Ripk3−/− mice develop lymphoproliferation resembling that caused by the Fas mutant in lpr mice (51), one can argue that Fas triggers necroptosis of Fadd−/− T cells through RIPK3.”
Necroptosis in development and diseasesPreprint
Shan, B., Pan, H., Najafov, A., & Yuan, J. (2018) · Genes & Development · doi:10.1101/gad.312561.118 · Cited by 345 · see citing works
“…and casp8−/−mlkl−/− double-deficient mice were viable and matured into fertile adults, they rapidly developed severe lymphadenopathy similar to FASL- or FAS-deficient mice (Watanabe-Fukunaga et al. 1992; Kaiser et al. 2011; Oberst et al. 2011; Dillon et al. 2012; Alvarez-Diaz et al. 2016).”
BackgroundRipk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury
Zhou, H., Zhu, P., Guo, J. X., Hu, N., Wang, S., Li, D., Hu, S., Ren, J. T., Cao, F., & Chen, Y. (2017) · Redox Biology · doi:10.1016/j.redox.2017.07.007 · Cited by 313 · see citing works
“By contrast, the amplification of caspase8-dependent apoptosis could cleave and abolish Ripk1/Ripk3 signals, preventing consequent necroptosis [43,44].”
BackgroundWidespread Mitochondrial Depletion via Mitophagy Does Not Compromise Necroptosis
Tait, S. W. G., Oberst, A., Quarato, G., Milasta, S., Haller, M., Wang, R., Karvela, M., Ichim, G., Yatim, N., Albert, M. L., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.034 · Cited by 303 · see citing works
“…1 (TNFR1) can lead either to apoptosis through activation of Caspase-8 or to programmed necrosis via RIPK1RIPK3 signaling (He et al., 2009), and the latter is inhibited by the action of a heterodimer of Caspase-8 and the Caspase-8like molecule c-FLIPL (Dillon et al., 2012; Oberst et al., 2011).”
InfluentialSelf-citationRIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis
Orozco, S., Yatim, N., Werner, M. R., Tran, H., Gunja, S. Y., Tait, S. W., Albert, M. L., Green, D. R., & Oberst, A. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.76 · Cited by 294 · see citing works
Self-citationRoles 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 290 · see citing works
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 · see citing works
Mihaly, S. R., Ninomiya‐Tsuji, J., & Morioka, S. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.123 · Cited by 294 · see citing works
“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).”
BackgroundPANoptosis: A Unique Innate Immune Inflammatory Cell Death Modality
Nagakannan, P., & Kanneganti, T. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2200508 · Cited by 291 · see citing works
Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer
Annibaldi, A., & Meier, P. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.11.002 · Cited by 287 · see citing works
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 280 · see citing works
“Fadd mice exhibit embryonic lethality that is reverted with loss of RIPK3 (29).”
BackgroundSelf-citationRegulated 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 276 · see citing works
“This study suggested that cross-regulation of RIPK3dependent signaling (including necroptosis) is controlled by the enzymatic activity of the FADDcaspase-8-cFLIPL complex and by cFLIP inhibition of RIPK3-independent apoptotic activity of the FADD-caspase-8 complex (Dillon et al. 2012).”
BackgroundHughes, 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 · see citing works
“In addition to its key role in apoptosis, caspase-8 has a survival role as it is required for embryonic development (Dillon et al., 2012; Varfolomeev et al., 1998), immune cell proliferation (Salmena et al.”
TNFR1-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 261 · see citing works
“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).”
BackgroundMolecular 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 · see citing works
“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].”
BackgroundHOIP 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 · see citing works
Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
Kang, S., Fernandes‐Alnemri, T., Rogers, C., Mayes, L., Wang, Y., Dillon, C. P., Roback, L., Kaiser, W. J., Oberst, A., Sagara, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms8515 · Cited by 255 · see citing works
“Given that FADD-or caspase-8 deficiency is embryonic lethal 19, 20, 21 and unleashes RIPK3-mediated necroptosis, we employed macrophages from either FADD/ RIPK3 or caspase-8/RIPK3 double knockout (DKO) mice 22, 23, 24 .”
Self-citationGlutathione 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 · see citing works
“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 247 · see citing works
RIP kinases as modulators of inflammation and immunity
He, S., & Wang, X. (2018) · Nature Immunology · doi:10.1038/s41590-018-0188-x · Cited by 246 · see citing works
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 246 · see citing works
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 243 · see citing works
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 · see citing works
“While deletion of RIPK3 does not promote survival of cFLIP-deficient mice, Cflar / Fadd / Ripk3 / mice are present at the expectedMendelian ratios at weaning (Dillon et al., 2012).”
BackgroundInfluentialSelf-citationDeath 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 243 · see citing works
“This lethality could only be reversed by concomitant deficiency in RIP3 and FADD but not when either factor was absent individually (Dillon et al. 2012).”
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 238 · see citing works
“The former isoform blocks caspase-8 to a degree that is sufficient to cleave and thus inactivate RIP1 but is insufficient to promote the activation of procaspase-3 to caspase-3 (55, 67, 221, 239).”
BackgroundAn Inflammatory Perspective on Necroptosis
Kearney, C. J., & Martin, S. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.02.024 · Cited by 227 · see citing works
Origin 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 210 · see citing works
LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis
Peltzer, N., Darding, M., Montinaro, A., Dráber, P., Draberova, H., Kupka, S., Rieser, E., Fisher, A. D., Hutchinson, J. C., Taraborrelli, L., et al. (2018) · Nature · doi:10.1038/s41586-018-0064-8 · Cited by 201 · see citing works
Molecular 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 203 · see citing works
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 199 · see citing works
Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis
Hirsova, P., & Gores, G. (2014) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2014.11.005 · Cited by 184 · see citing works
Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis
Wegner, K. W., Saleh, D., & Degterev, A. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.005 · Cited by 190 · see citing works
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 188 · see citing works
“In contrast to FADD- and caspase-8-deficient mice, cFLIP- and RIPK1-deficient mice are not rescued by RIPK3 deficiency, and cFLIP-deficient mice only survive when FADD and RIPK3 are concomitantly deleted on a triple knockout background (66).”
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 189 · see citing works
Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling
Peltzer, N., Darding, M., & Walczak, H. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.01.006 · Cited by 184 · see citing works
Necroptosis: an alternative cell death program defending against cancer
Chen, D., Yu, J., & Zhang, L. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.03.003 · Cited by 182 · see citing works
Chen, J., Kos, R., Garssen, J., & Redegeld, F. A. (2019) · Cells · doi:10.3390/cells8121486 · Cited by 178 · see citing works
“Nonetheless, the FADD-pro-caspase-8-cFLIPL complex inhibits activation of RIPK3, which subsequently inhibits necroptosis [26].”
BackgroundThe 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 176 · see citing works
“More recent studies of conditional cFLIP knockout mice describe a role for cFLIP in regulating both apoptosis and necroptosis pathways, since the lethal phenotype of cFLIP knockout mice is rescued by co-deletion of RIPK3 and FADD, but not by either alone [98].”
BackgroundFLIP 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 172 · see citing works
“Whole body KO mice Cflip ́{ ́ Embryonic lethality [82] Cflip-l+46 mutant Embryonic lethality [83] Cflip ́{ ́Ripk3 ́{ ́ Embryonic lethality [84] Cflip ́{ ́Fadd ́{ ́Ripk3 ́{ ́ Normal development [84]”
BackgroundAutophagy and apoptosis cascade: which is more prominent in neuronal death?
Gupta, R. V., Ambasta, R. K., & Kumar, P. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04004-4 · Cited by 171 · see citing works
Haverkamp, J. M., Smith, A. M., Weinlich, R., Dillon, C. P., Qualls, J. E., Neale, G. A. M., Koss, B. S., Kim, Y., Bronte, V., Herold, M. J., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.020 · Cited by 167 · see citing works
“RIPK3 and FADD-deficient mice and their compound crosses have been described (Dillon et al., 2012; Weinlich et al., 2013).”
Self-citationNecrosome 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 · see citing works
“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 · see citing works
“Mice lacking Fadd or Casp8 are embryonically lethal but survive past weaning when either one of the necroptosis-mediating genes, Ripk3 or Mlkl, are coablated (Alvarez-Diaz et al., 2016; Dillon et al., 2012; Dillon et al., 2014; Kaiser et al., 2011; Oberst et al., 2011), showing that another function of the FADD-Caspas…”
BackgroundSelf-citationProtective 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 · see citing works
“, 2011), and can also sensitize to FADD-caspase-8dependent apoptosis (Dillon et al., 2012; Irmler et al., 1997; Yeh et al., 2000).”
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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 153 · see citing works
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 154 · see citing works
“Because apoptosis is indispensable for mammalian development [7, 8], apoptosis is not an ideal target for controlling inflammation.”
BackgroundProgrammed necrosis and necroptosis signalling
Feoktistova, M., & Leverkus, M. (2014) · FEBS Journal · doi:10.1111/febs.13120 · Cited by 153 · see citing works
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 149 · see citing works
“Fadd / Rip3 / mice and Fadd / Rip3 / Flip / mice [91] also develop into viable adults.”
BackgroundSurviving apoptosis: life–death signaling in single cells
Flusberg, D. A., & Sorger, P. K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.03.003 · Cited by 149 · see citing works
Harnessing 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 144 · see citing works
Zhang, Q., Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. (2013) · Autophagy · doi:10.4161/auto.23691 · Cited by 142 · see citing works
Linear ubiquitination in immunity
Shimizu, Y., Taraborrelli, L., & Walczak, H. (2015) · Immunological Reviews · doi:10.1111/imr.12309 · Cited by 135 · see citing works
“Interestingly, their cleavage by the caspase-8/c-FLIP heterodimer, which does not induce apoptosis, appears to be required to block necroptosis (25, 26).”
BackgroundNonapoptotic cell death in acute kidney injury and transplantation
Linkermann, A. (2016) · Kidney International · doi:10.1016/j.kint.2015.10.008 · Cited by 140 · see citing works
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 143 · see citing works
CRISPR/Cas9 Screens Reveal Epstein-Barr Virus-Transformed B Cell Host Dependency Factors
Ma, Y., Walsh, M. J., Bernhardt, K., Ashbaugh, C. W., Trudeau, S. J., Ashbaugh, I. Y., Jiang, S., Jiang, C., Zhao, B., Root, D. E., et al. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.04.005 · Cited by 137 · see citing works
“cFLIP-L heterodimerizes with caspase-8, blocks the extrinsic pathway, and together with FADD, blocks RIP3-dependent necroptosis (Dillon et al., 2012).”
BackgroundKearney, 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 132 · see citing works
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 136 · see citing works
Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control
Sangiuliano, B. A., Pérez-Sosa, M., Moreira, D., & Belizário, J. E. (2014) · Mediators of Inflammation · doi:10.1155/2014/821043 · Cited by 136 · see citing works
“Mice deficient in FADD or caspase-8 die during embryogenesis; however, mice with triple deletion of FADD, caspase-8, and RIPK3 are viable [39, 40, 44, 45].”
BackgroundThe 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 127 · see citing works
Self-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 143 · see citing works
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A long-awaited merger of the pathways mediating host defence and programmed cell death
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- Authors
- Dillon, C. P., Oberst, A., Weinlich, R., Janke, L. J., Kang, T.-B., Ben-Moshe, T., Mak, T. W., Wallach, D., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Konkuk University (KR)
- Weizmann Institute of Science (IL)
- University Health Network (CA)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 1
- Issue
- 5
- Pages
- 401-407
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3366463
- OpenAlex
- W2090234862
- Cited by
- 331
- References
- 34
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 18 · 2023: 13 · 2022: 21 · 2021: 24 · 2020: 17 · 2019: 21 · 2018: 26 · 2017: 25 · 2016: 35 · 2015: 33 · 2014: 49 · 2013: 26 · 2012: 3
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (R01GM052735)
- National Institute of Allergy and Infectious Diseases (R01AI044828, R01AI040646, AI44828, R01AI047891, R37AI044828)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- FADD, caspase-8, c-FLIP, RIPK3, death receptor signaling, apoptosis, necrosis, embryonic lethality, double knockout mice, programmed cell death, caspase-8 activation
- MeSH terms
- Animals, Necrosis, Signal Transduction, Apoptosis, Gene Deletion, Mice, Knockout, Embryonic Development, Mice, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, CASP8 and FADD-Like Apoptosis Regulating Protein
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