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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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The Prevalence of TNFα-Induced Necrosis over Apoptosis Is Determined by TAK1-RIP1 Interplay
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“Downstream of death receptors, Toll-like receptors, or other sensors, RIP3 activation is tightly regulated by phosphorylation (12–15) or caspase-mediated cleavage (16, 17).”
BackgroundThe many faces of tumor necrosis factor signaling in the intestinal epithelium
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BackgroundViral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis
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“These 322 findings match previous work in other systems where necroptosis is evident 323 when caspases have been rendered non-functional (55-57).”
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“Interestingly, high levels of RIPK1 and RIPK3 have been described for PDAC, as well as their upregulation following treatment with gemcitabine.”
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Self-citationRIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice
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“In support of this possibility, cFLIP has been shown to trigger a RIPK1/RIPK3-dependent necroptosis pathway that results in cell death.(45,46)”
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“In addition, caspase-8 and FADD were reported to form a salvage pathway from necroptosis dependent on RIP1 kinase (27, 28).”
BackgroundRIPK3 regulates p62–LC3 complex formation via the caspase-8-dependent cleavage of p62
Matsuzawa, Y., Oshima, S., Nibe, Y., Kobayashi, M., Maeyashiki, C., Nemoto, Y., Nagaishi, T., Okamoto, R., Tsuchiya, K., Nakamura, T., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.11.075 · Cited by 44
Execution of RIPK3-regulated necrosis
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ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1
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Self-citationCharacterization of the Ripoptosome and Its Components
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“It was possible to show that the embryonic lethality of caspase-8 deficiency could be rescued with the additional deletion of RIP3, which is the key player of necroptotic cell death (Kaiser et al., 2011; Oberst et al., 2011).”
BackgroundThe Mechanisms of Chansu in Inducing Efficient Apoptosis in Colon Cancer Cells
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Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity
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“Mice deficient for caspase-8 are protected from embryonic lethality by concomitant loss of RIPK3 or MLKL, revealing that caspase-8 prevents necroptosis during development (38, 58, 59).”
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“Our observation that inflammatory proteins became activated in the absence of RIPK3 and apparently without phosphorylation of RIPK1 casts doubt on the possibility that CYLD cleavage is a player in the regulation of this process.”
BackgroundInfluentialCutting Edge: TAK1 Safeguards Macrophages against Proinflammatory Cell Death
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“Similarly to previous reports (32, 33), Casp8Ripk3 mice developed an autoimmune lymphoproliferative syndrome–like phenotype with age, exemplified by the appearance of splenomegaly and lymphadenopathy (Supplemental Fig.”
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“Caspase-8 prevents RIP3dependent necroptosis through the disruption of formation of a stable necrosome complex [16], and the levels of caspase-8 are reduced in the inflamed tissues of patients with active IBD [11].”
BackgroundProgrammed Cell Death in Immune Defense: Knowledge and Presumptions
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Regulation and pathophysiological role of epithelial turnover in the gut
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“Germline inactivation of these genes results in embryonic lethality that can be rescued by deletion of RIPK1 or RIPK3 (Kaiser et al. 2011; Oberst et al. 2011; Zhang et al. 2011; Dillon et al. 2012).”
BackgroundTesticular torsion and reperfusion: evidences for biochemical and molecular alterations
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“…the caspase family has been classified by their roles, as caspases (caspase-3, -6, -7, -8, and -9 in mammals) participating in apoptosis and those (caspase-1, -4, -5, and -12 in humans and caspase-1, -11, and -12 in mice) involving in inflammation (McIlwain et al. 2013; Oberst et al. 2011).”
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“spontaneous cell death and inflammation in lymphocytes (42, 43, 48), keratinocytes (36), and intestinal epithelial cells (49, 50).”
BackgroundBrentnall, M., Weir, D. B., Rongvaux, A., Marcus, A. I., & Boise, L. (2014) · Journal of Cell Science · doi:10.1242/jcs.135137 · Cited by 38
“Caspase-8 prevents RIPKmediated necrosis, whereas a recent report demonstrated that caspase-10 prevents autophagic death of myeloma cells by cleaving the Bcl2-interacting protein BCLAF1 (Green et al., 2011; Kaiser et al., 2011; Lamy et al., 2013; Oberst et al., 2011).”
Backgroundp53 at the crossroad between mitochondrial reactive oxygen species and necroptosis
Rius‐Pérez, S. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.07.022 · Cited by 37
Schworer, S. A., Smirnova, I., Валерьевна, К. И., Bagina, U., Churova, M. V., Fowler, T., Roy, A. L., Degterev, A., & Poltorak, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.547547 · Cited by 37
Hojo, T., Siemieniuch, M., Łukasik, K., Piotrowska-Tomala, K. K., Jończyk, A. W., Okuda, K., & Skarzynski, D. J. (2016) · Scientific Reports · doi:10.1038/srep38211 · Cited by 36
“Cellular FLICE-like inhibitory protein (cFLIP) may be a candidate intracellular factor regulating RIPK activation and necroptosis 30 .”
Ryan, F., Khodagholi, F., Dargahi, L., Minai‐Tehrani, D., & Ahmadiani, A. (2018) · Neurotoxicity Research · doi:10.1007/s12640-017-9861-3 · Cited by 37
“But, upon inhibition or suppression of caspase-8, necroptotic cascade is triggered (Kaiser et al. 2013; Kaiser et al. 2011; Oberst et al. 2011).”
BackgroundTargeting Wnt Signaling via Notch in Intestinal Carcinogenesis
Kaemmerer, E., Jeon, M. K., Berndt, A., Liedtke, C., & Gaßler, N. (2019) · Cancers · doi:10.3390/cancers11040555 · Cited by 36
“The complex function of Casp8 in intestinal mucosa includes regulation of TNF-α-induced epithelial necroptosis [65] with inhibition of RIPK3-dependent necrosis [66] and is involved in the functional complementation between FADD and RIPK1 [67].”
BackgroundThe Interplay Between Autophagy and Regulated Necrosis
Zhang, L., Cui, T., & Wang, X. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0110 · Cited by 39
“Deletion of c-FLIP L sensitized hepatocytes to TNF a -induced RIPK1/RIPK3-dependent ne-croptosis (Oberst et al, 2011).”
Liccardi, G., & Annibaldi, A. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01061-5 · Cited by 37
“In fact, the embryonic lethality caused in mice by the deletion of Caspase-8 is prevented by the co-deletion of RIPK3 [54, 55].”
Silke, J., & Strasser, A. (2013) · Science Signaling · doi:10.1126/scisignal.2003845 · Cited by 37
Gerges, S., Rohde, K., & Fulda, S. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.02.040 · Cited by 35
“fmk BV6/5AC-treated ALL cells undergo necroptotic cell death, since caspase inhibition has previously been reported to cause a switch from apoptotic to necroptotic cell death [9].”
BackgroundResultInfluentialOrme, M. H., Liccardi, G., Moderau, N., Feltham, R., John, S. W., Tenev, T., Aram, L., Wilson, R., Bianchi, K., Morris, O., et al. (2016) · Nature Communications · doi:10.1038/ncomms10972 · Cited by 35
Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3
Lee, S.-Y., Kim, H., Li, C. M., Kang, J., Najafov, A., Jung, M., Kang, S., Wang, S., Yuan, J., & Jung, Y. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2146-4 · Cited by 36
Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage
Rusu, I., Mennillo, E., Li, Z., Bain, J. L., Sun, X., Ly, K., Rosli, Y. Y., Naser, M., Wang, Z., Advincula, R., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154993 · Cited by 37
RIP1-mediated regulation of lymphocyte survival and death responses
Zhang, J., Zhang, H., Li, J., Rosenberg, S., Zhang, E. C., Zhou, X., Qin, F., & Farabaugh, M. E. (2011) · Immunologic Research · doi:10.1007/s12026-011-8249-3 · Cited by 35
“Interestingly, RIP3 deficiency completely rescues the embryonic defects in caspase 8−/− mice (75, 76).”
BackgroundRIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation
Tran, H. T., Kratina, T., Coutansais, A., Michalek, D., Hogan, B. M., Lawlor, K. E., Vince, J. E., Silke, J., & Lalaoui, N. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01281-x · Cited by 33
“Casp8 -/- and Casp8 C362A/C362A mice are lethal due to uncontrolled RIPK3-dependent necroptosis [9, 23, 24, 32, 33].”
BackgroundGao, X., Ma, C., Liang, S., Chen, M., He, Y. Z., & Lei, W. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5398 · Cited by 34
“It serves as a precursor in NLRP3 inflam‑ masome activation, thereby inducing pyroptosis (104).”
BackgroundExploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies
Fulda, S. (2012) · Leukemia · doi:10.1038/leu.2012.4 · Cited by 36
Dying to protect: cell death and the control of T‐cell homeostasis
Li, K., Shanmuganad, S., Carroll, K. R., Katz, J. D., Jordan, M. B., & Hildeman, D. A. (2017) · Immunological Reviews · doi:10.1111/imr.12538 · Cited by 34
c-FLIP is a target of the E3 ligase deltex1 in gastric cancer
Hsu, T.-S., Mo, S.-T., Hsu, P., & Lai, M. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0165-6 · Cited by 34
Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis
Coornaert, I., Hofmans, S., Devisscher, L., Augustyns, K., der Veken, P. V., Meyer, G. R. Y. D., & Martinet, W. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1457644 · Cited by 35
Caspase-8 modulates physiological and pathological angiogenesis during retina development
Tisch, N., Freire-Valls, A., Yerbes, R., Paredes, I., Porta, S. L., Wang, X., Martín‐Pérez, R., Castro, L., Wong, W. W.-L., Coultas, L., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci122767 · Cited by 35
“Casp-8 inhibits RIPK3 (12), and it has recently been shown that RIPK3 regulates vessel permeability via p38 in ECs (22).”
Lee, S., Lee, E., Kang, D. H., Lee, J., Hong, S. H., Jeong, W., & Kang, S. W. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00642-7 · Cited by 34
The role of necroptosis, an alternative form of cell death, in cancer therapy
Yu, X., Deng, Q., Bode, A. M., Dong, Z., & Cao, Y. (2013) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2013.811180 · Cited by 34
Classical apoptotic stimulus, staurosporine, induces lytic inflammatory cell death, PANoptosis
Sarkar, R., Choudhury, S. M., & Kanneganti, T. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107676 · Cited by 33
Xia, Y., Wang, Y., Chen, K., Zhang, M., Jiang, Q., & Xu, T. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156551 · Cited by 35
IAP gene deletion and conditional knockout models
Silke, J., & Vaux, D. L. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.12.004 · Cited by 32
Sharma, D., Sharma, B. R., Vogel, P., & Kanneganti, T. (2016) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.10.015 · Cited by 31
Feltham, R., & Silke, J. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.67 · Cited by 33
Cann, F. L., Delehouzé, C., Leverrier, S., Filliol, A. A., Comte, A., Delalande, O., Desban, N., Baratte, B., Gallais, I., Piquet‐Pellorce, C., et al. (2017) · FEBS Journal · doi:10.1111/febs.14176 · Cited by 36
Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells
Feldmann, F., Schenk, B., Martens, S., Vandenabeele, P., & Fulda, S. (2017) · Oncotarget · doi:10.18632/oncotarget.19919 · Cited by 34
“In apoptosis-resistant cancers therapeutic induction of necroptosis may be of particular interest, as activated caspase-8 has been shown to cleave and thus inactivate RIP1 [10].”
BackgroundLi, D., Ai, Y., Guo, J., Dong, B., Lin, L., Cai, G., Chen, S., Xu, D., Wang, F., & Wang, X. (2020) · eLife · doi:10.7554/elife.61564 · Cited by 33
“…CSNK1G2 blocked necroptosis caused by the FKBP-binding small molecule induced dimerization of an FKBP-F36V-RIP3 fusion protein (Li et al., 2020; Orozco et al., 2014), while the kinase-dead CSNK1G2 (K75A) mutants did not, indicating that CSNK1G2 inhibits necroptosis by directly preventing RIP3…”
BackgroundTherapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?
van Schaik, T., Chen, K., & Shah, K. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.678562 · Cited by 37
“However, if the caspase pathway is defective in tumor cells, necroptosis will be activated (100).”
BackgroundEndotheliopathy in the metabolic syndrome: Mechanisms and clinical implications
Furuta, K., Tang, X., Islam, S., Tapia, A., Chen, Z. B., & Ibrahim, S. H. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108372 · Cited by 36
Prix Fixe: Efferocytosis as a Four-Course Meal
Martinez, J. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_467 · Cited by 36
“Furthermore, inactive RIPK1 can block RIPK3 activity, even when RIPK3 is activated independently of RIPK1 (Oberst et al. 2011).”
BackgroundInfluential
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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