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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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“lymphproliferation mutation mouse model. lpr mice carry functional mutation in the Fas gene which causes autoimmune lymphocytes accumulation necroptosis a form of necrotic programmed cell death dependent on oligomerization of RIP1/RIP3 that that results in release of cellular contents and an acute inflammatory respons…”
BackgroundInfluentialAn Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages
de Vasconcelos, N. M., Opdenbosch, N. V., Gorp, H. V., Martín‐Pérez, R., Zecchin, A., Vandenabeele, P., & Lamkanfi, M. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107959 · Cited by 84
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“Currently, sensitization to necroptosis is achieved through a genetic defect compromising FADD-caspase-8 signaling and thus inhibiting apoptosis [68-71]; and inhibition of caspase-8 causes necroptosis [24], suggesting that whether a cell dies by apoptosis or necroptosis depends on caspase-8 activity.”
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“The resultant p43/41-caspase-8:p43-cFLIP L heterodimer is catalytically active toward the necroptosis-regulatory proteins RIPK1, RIPK3, and CYLD to suppress their activity (Micheau et al , 2002; Feng et al , 2007; Oberst et al , 2011; O’Donnell et al , 2011; Newton et al , 2019).”
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“Knockout of caspase-8 is embryonic lethal in mice, but animals double knockout for caspase-8/RIPK3 or caspase-8/ MLKL develop normally (Kaiser et al., 2011; Oberst et al., 2011).”
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“While apoptosis is inhibited, noncanonical Caspase-8/cFLIPL dimer functioning results in the cleavage of RIP1/RIP3 for simultaneous inhibition of necroptosis.(25) Loss of cFLIPL or activation of cFLIPS within the ripoptosome induces caspase-dependent apoptosis or caspase-”
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Oncolytic Viruses as Anticancer Vaccines
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“It has been demonstrated that the highly specific caspase-8 inhibitor vICA, encoded by cytomegalovirus, predisposes to RIP3-dependent necrosis (31).”
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“In line with these findings, caspase activity has recently been reported to negatively regulate necroptosis by cleaving RIP1 [10].”
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“The dual function of caspase 8 in initiation of apoptosis and suppression of RIPK3dependent necrosis (32–34), which has been shown to be required for normal murine embryonic development and survival (35) is well documented.”
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MLKL regulates necrotic plasma membrane permeabilization
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cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
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“A current hypothesis is that activity of the caspase-8/ cFLIPL heterodimer within different signaling platforms is able to inactivate pronecroptotic signaling (Geserick et al., 2009; Oberst et al., 2011).”
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Verdonck, S., Nemegeer, J., Vandenabeele, P., & Maelfait, J. (2021) · Trends in Microbiology · doi:10.1016/j.tim.2021.11.011 · Cited by 76
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c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis
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“The necroptotic pathway, which is triggered by TNF-a or viral infection, largely depends on two related kinases, receptor-interacting serine-threonine kinase 1 (RIPK1) and RIPK3 (15–18).”
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“Necroptosis plays a critical role in regulating the baseline CD8 T lymphocyte pool, as gene-knockout mice that lack necroptosis (Casp8 / Ripk3 / ) are characterized by a phenotype of severe lymphadenopathy, splenomegaly, and increased accumulation of aberrant B220 CD3 T lymphocytes (Oberst et al., 2011).”
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The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death
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“caspase-8 is able to cleave RIPK1/3 and inhibit necroptosis [5, 103].”
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Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death
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Apoptotic and Nonapoptotic Caspase Functions in Animal DevelopmentPreprint
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“Deletion of RIPK1 or RIPK3 rescued lethality of FADD or caspase-8 deletion (Kaiser et al. 2011; Oberst et al. 2011; Zhang et al. 2011).”
BackgroundTrue Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity
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“TNFR1, as well as the Fas/CD95 and TRAIL death receptors, control NF-kB activation, extrinsic apoptosis, and programmed necrosis by DD signal transduction, functioning in collaboration with death effector domain (DED) interactions (6) mediated via a critical complex consisting of Casp8, FLIP, FADD, and RIP1 (denoted “…”
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A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes
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“Furthermore, siRNA-mediated silencing of c-FLIPL sensitizes cells to TNF-induced RIP1/RIP3-dependent necroptosis.(8) However, the role of c-FLIPL in necroptosis has yet to be studied in primary T cells in a genetically deficient model.”
BackgroundQuantitative and Dynamic Catalogs of Proteins Released during Apoptotic and Necroptotic Cell Death
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Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus
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“However, as MLKL-deficient (Murphy et al. 2013) or RIPK3-deficient (Newton et al. 2004) mice do not show developmental phenotypes, one would need to speculate that BAX/BAK can compensate well for their absence in cell death initiation during embryogenesis.”
BackgroundInfluentialGeneration of small molecules to interfere with regulated necrosis
Degterev, A., & Linkermann, A. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2198-x · Cited by 72
“In this respect, the dispensability of caspase-8 in most tissues may support this assumption [14, 15].”
BackgroundRegression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice
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“…is protective against apoptosis and renders cells highly susceptible to RIP3-mediated necroptotic cell death (He et al., 2009; Günther et al., 2011; Kaiser et al., 2011; Oberst et al., 2011), highlighting the potential to induce tumor cell necroptosis in apoptosis-resistant cancer patients.”
The role of regulated necrosis in endocrine diseases
Tonnus, W., Belavgeni, A., Beuschlein, F., Eisenhofer, G., Faßnacht, M., Kroiß, M., Krone, N. P., Reincke, M., Bornstein, S. R., & Linkermann, A. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00499-w · Cited by 74
Knowledge Mapping of Necroptosis From 2012 to 2021: A Bibliometric Analysis
Zhang, J., Song, L., Jia, J., Tian, W., Lai, R., Zhang, Z., Li, J., Ju, J., & Xu, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.917155 · Cited by 73
“The pathways of necroptosis and apoptosis are tightly linked through caspase-8 (51, 52), which not only is a typical activator of extrinsic apoptosis but also inhibits necroptosis through the cleavage of RIPK1 and possibly RIPK3 (53, 54).”
BackgroundRegulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections
Zhang, G., Wang, J., Zhao, Z., Xin, T., Fan, X., Shen, Q., Raheem, A., Lee, C. R., Jiang, H., & Ding, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05066-3 · Cited by 75
“The presence of caspase-8 in the necrosome can prevent the interaction of RIP1 and RIP3 via the direct cleavage of these two kinases [50, 62, 63].”
BackgroundMonie, T. P., & Bryant, C. E. (2015) · Immunological Reviews · doi:10.1111/imr.12284 · Cited by 74
“This phenotype can be rescued by the simultaneous removal of Ripk3 (receptor-interacting serine/threonine-protein kinase 3), consistent with a role for caspase-8 in controlling RIPK3dependent cell death processes (3, 4).”
BackgroundThe inflammatory role of phagocyte apoptotic pathways in rheumatic diseases
Cuda, C. M., Pope, R. M., & Perlman, H. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2016.132 · Cited by 78
Khan, M. B., Lin, J., Wang, B., Chen, C., Huang, Z., Tian, Y., Yuan, Y., & Bu, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.968165 · Cited by 72
Ye, Y., Wang, H., Yu, L., Tashiro, S., Onodera, S., & Ikejima, T. (2012) · International Immunopharmacology · doi:10.1016/j.intimp.2012.08.003 · Cited by 73
Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation
Wu, Y., Kuo, W.-C., Wu, Y.-J., Yang, K.-T., Chen, S.-T., Jiang, S.-T., Gordy, C. L., He, Y., & Lai, M.-Z. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.165 · Cited by 75
“c-FLIP is an inhibitor of death receptor-mediated apoptosis and necrosis.(1,30,31) Complete deletion of c-FLIP leads to significant death of macrophages.”
BackgroundNecroptosis in cancer: An angel or a demon?
Wang, T., Jin, Y., Yang, W., Zhang, L., Jin, X., Liu, X., He, Y., & Li, X. (2017) · Tumor Biology · doi:10.1177/1010428317711539 · Cited by 72
Berry, C. T., Liu, X., Myles, A., Nandi, S., Chen, Y. H., Hershberg, U., Brodsky, I. E., Cancro, M. P., Lengner, C. J., May, M. J., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.038 · Cited by 71
A Non-canonical PDK1-RSK Signal Diminishes Pro-caspase-8-Mediated Necroptosis Blockade
Yang, Z., Wu, X., He, P., Wang, X., Wu, J., Ai, T., Zhong, C., Wu, X., Yu, C., Zhu, R., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.09.004 · Cited by 70
Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks
Ivanisenko, N. V., Seyrek, K., Hillert-Richter, L. K., König, C., Espe, J., Bose, K., & Lavrik, I. N. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.12.002 · Cited by 74
Exploring TNFR1: from discovery to targeted therapy development
Li, Y., Ye, R., Dai, H., Lin, J., Cheng, Y., Zhou, Y., & Lu, Y. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06122-0 · Cited by 90
Figgett, W. A., Fairfax, K. A., Vincent, F. B., Page, M. A. L., Katik, I., Deliyanti, D., Quah, P. S., Verma, P., Grumont, R. J., Gerondakis, S., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.019 · Cited by 73
“This pathway promotes cell survival and proliferation (Hyer et al., 2006) as well as the suppression of RIPK3-mediated necroptosis (Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundSiniscalco, D., Sapone, A., Giordano, C., Cirillo, A., de Novellis, V., de Magistris, L., Rossi, F., Fasano, A., Maione, S., & Antonucci, N. (2011) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-011-1373-z · Cited by 70
“Beside its role in apoptosis, caspase-8 also plays a role in T cell activation (Oberst et al. 2011).”
BackgroundTRAILblazing Strategies for Cancer Treatment
Kretz, A.-L., Trauzold, A., Hillenbrand, A., Knippschild, U., Henne‐Bruns, D., von Karstedt, S., & Lemke, J. (2019) · Cancers · doi:10.3390/cancers11040456 · Cited by 71
Wu, X., Tian, L., Li, J., Zhang, Y., Han, V. K. M., Li, Y., Xu, X., Li, H., Chen, X., Chen, J., et al. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m112.019091 · Cited by 72
“caspase-8-deficient mice is rescued by RIP3 deletion (9, 10).”
BackgroundCD95 in cancer: tool or target?
Martín-Villalba, A., Llorens-Bobadilla, E., & Wollny, D. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.03.002 · Cited by 70
Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation
Zhang, J., Webster, J. D., Dugger, D. L., Goncharov, T., Roose‐Girma, M., Hung, J., Kwon, Y. C., Vucic, D., Newton, K., & Dixit, V. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.111 · Cited by 71
Regulation of cell death in the cardiovascular system
Patel, P., & Karch, J. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.11.005 · Cited by 74
Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy
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“A change in cell death profile, apoptosis/autophagy and vice versa, following photodynamic treatment has been also demonstrated after 5-ALA photosensitizition of the U2OS osteosarcoma cell line deficient in receptor-interacting protein 3 (RIP3), a key molecule in necroptosis [137 139] and apoptosis [140,141].”
BackgroundNecroptotic signaling in adaptive and innate immunity
Lu, J. V., Chen, H. C., & Walsh, C. M. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.07.003 · Cited by 71
“It has been suggested that the caspase 8-c-FLIPL heterodimer cleaves RIP3 [26] and CYLD to promote apoptosis and prevent necroptosis.”
BackgroundAkt Regulates TNFα Synthesis Downstream of RIP1 Kinase Activation during Necroptosis
McNamara, C. R., Ahuja, R., Osafo-Addo, A. D., Barrows, D., Kettenbach, A. N., Skidan, I. N., Teng, X., Cuny, G. D., Gerber, S. A., & Degterev, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056576 · Cited by 69
“(A) FADD-deficient Jurkat cells were treated with TNFa in the presence of Nec-1 or Akt inh VIII.”
BackgroundInfluentialAugmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis
Bailey, L. J., Alahari, S., Tagliaferro, A., Post, M., & Caniggia, I. (2017) · Cell Death and Disease · doi:10.1038/cddis.2016.483 · Cited by 70
“5 and this is mediated by RIP3, a critical kinase comprising the necrosome complex.(25,26) However, the authors did not comment on whether there was a placental phenotype.”
BackgroundWeinlich, R., Dillon, C. P., & Green, D. R. (2011) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.09.002 · Cited by 69
Self-citationRIP3 induces ischemic neuronal DNA degradation and programmed necrosis in rat via AIF
Xu, Y., Wang, J., Song, X., Qu, L., Wei, R., He, F., Wang, K., & Luo, B. (2016) · Scientific Reports · doi:10.1038/srep29362 · Cited by 68
Pyroptosis: The missing puzzle among innate and adaptive immunity crosstalk
Hachim, M. Y., Khalil, B. A., Elemam, N. M., & Maghazachi, A. A. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mir0120-625r · Cited by 71
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Safferthal, C., Rohde, K., & Fulda, S. (2016) · Oncogene · doi:10.1038/onc.2016.310 · Cited by 68
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“It is possible that the heteromer of caspase-8 and cFLIPL has a limited or distinct activity that contributes to signaling in an as yet undefined manner and it also may cleave RIPK1 [8] Certainly over-expression of cFLIPL limits recruitment of RIPK1 into complex 2 [5].”
Eytan, D. F., Snow, G. E., Carlson, S. G., Derakhshan, A., Saleh, A., Schiltz, S., Cheng, H. W., Mohan, S., Cornelius, S., Coupar, J. F., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-3317 · Cited by 72
“Binding of TNFα, TRAIL or other death agonists to their receptors typically leads to cell death via FADD through the activation of caspase-8 and induction of apoptosis, or alternatively, activation of RIP kinase 1 (RIPK1), MLKL, and induction of necroptosis (5-10).”
Determining the effector response to cell death
Rothlin, C. V., Hille, T. D., & Ghosh, S. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00456-0 · Cited by 69
Li, X., Li, F., Zhang, X., Zhang, H., Zhao, Q., Li, M., Wu, X., Wang, L., Liu, J., Wu, X., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00938-9 · Cited by 69
Striking a Balance: Autophagy, Apoptosis, and Necrosis in a Normal and Failing Heart
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“causes cleavage of RIPK1 and RIPK3 and destabilization of ripoptosome complexes (Feng et al., 2007; Oberst et al., 2011).”
BackgroundThe CD95/CD95L signaling pathway: A role in carcinogenesis
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The potential role of necroptosis in clinical diseases (Review)
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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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