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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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Caspase Functions in Cell Death and DiseasePreprint
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“Recently, three reports provided evidence that some of the defects associated with loss of caspase-8, and result in embryonic death, are not owing to impaired apoptosis but rather to defective suppression of receptor-interacting serinethreonine kinase 3 (RIPK3) -dependent necrosis (Kaiser et al. 2011; Oberst et al. 20…”
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Synchronized renal tubular cell death involves ferroptosis
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MethodSelf-citationMonocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span
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“However, in the absence of FLIP, activation of caspase-8 is not sufficient to prevent RIPK-dependent necrosis, even if apoptosis downstream from caspase-8 activation is blocked (Oberst et al. 2011).”
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Fritsch, M., Günther, S. D., Schwarzer, R., Albert, M., Schorn, F., Werthenbach, J. P., Schiffmann, L. M., Stair, N., Stocks, H., Seeger, J. M., et al. (2019) · Nature · doi:10.1038/s41586-019-1770-6 · Cited by 1,122
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Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy
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Necroptosis in development, inflammation and disease
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Self-citationProgrammed cell death as a defence against infection
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Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
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“This crucial interplay between the inhibition of caspase activity and RIPK1-and RIPK3-mediated necrotic cell death has been clearly demonstrated by the finding that genetic deletion of RIPK1 and/or RIPK3 rescues the lethality observed in caspase 8-deficient or FADD-deficient mice 86,87,106–108 .”
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Bedoui, S., Herold, M. J., & Strasser, A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0270-8 · Cited by 1,027
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Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL
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“This situation is reminiscent of work from Meylan et al. (29), where RIP1 and RIP3 were shown to differentially compete for RHIM-depen-dent binding with TRIF.”
BackgroundResultInfluentialA guide to cell death pathways
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“Furthermore, blocking RIPK1 kinase and necroptosis can suppress early embryonic lethality of Casp8 -null mice, Fadd -null mice, Abin1 -null mice and Tbk1 - null mice, suggesting that necroptosis may be involved in the removal of defective developing embryos 52,67,139,140 .”
Death by TNF: a road to inflammation
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Caspases in Cell Death, Inflammation, and Pyroptosis
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Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis
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“caspase-8 can suppress necroptosis is not fully understood, but it appears that its catalytic activity is necessary.(81)”
BackgroundCaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis
Zhang, T., Zhang, Y., Cui, M., Jin, L., Wang, Y., Lv, F., Liu, Y., Zheng, W., Shang, H., Zhang, J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4017 · Cited by 790
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“Likewise, the RIP3-dependent necroptosis resulting in lethality of Casp8−/− mice (Kaiser et al., 2011; Oberst et al., 2011) was not rescued loss of DAI (Figure S3D), and Casp8−/−DAI−/− embryos were phenotypically indistinguishable from Casp8−/− littermate embryos (data not shown).”
InfluentialCaspase‐8: regulating life and death
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“One possible explanation for this apparent paradox is that the RIP1-mediated signal, and possibly the induction of cFLIP [cellular FLICE (FADD-like IL-1β–converting enzyme)inhibitory protein], is particularly important for macrophage survival (25).”
BackgroundNecroptosis: a regulated inflammatory mode of cell death
Dhuriya, Y. K., & Sharma, D. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1235-0 · Cited by 752
“Hence, complex I is a crucial checkpoint for cell survival and necroptosis [31].”
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“5 (60), such an embryonic lethal phenotype is rescued by the concomitant absence of Ripk3 (56, 61).”
ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences
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Self-citationActivity of Protein Kinase RIPK3 Determines Whether Cells Die by Necroptosis or Apoptosis
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“The PtdSer receptor TIM4 has been demonstrated to play a critical role in the recognition and clearance of apoptotic cells in vivo (6).”
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Self-citationRegulated necrosis: disease relevance and therapeutic opportunities
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Live to die another way: modes of programmed cell death and the signals emanating from dying cells
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“Interestingly, in contrast to the proapoptotic caspase-8 homodimer, these heterodimers of caspase-8 and FLIPL have been shown to promote cell survival (Oberst et al. 2011; van Raam and Salvesen 2012).”
BackgroundRegulation of RIP1 kinase signalling at the crossroads of inflammation and cell death
Ofengeim, D., & Yuan, J. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3683 · Cited by 635
RIP3 Induces Apoptosis Independent of Pronecrotic Kinase Activity
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“We thank Tak Mak (University of Toronto) for cFLIP / MEF and Fadd / MEF, Astar Winoto (University of California Berkeley) for FADD antibody, Domagoj Vucic (Genentech) for BV6, and Andrew Oberst (University ofWashington) for cFLIP expression plasmids.”
BackgroundInfluentialFADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
Welz, P.-S., Wullaert, A., Vlantis, K., Kondylis, V., Fernández-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., & Pasparakis, M. (2011) · Nature · doi:10.1038/nature10273 · Cited by 594
RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
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“These in vitro results are in line with the recent reports on the in vivo role of caspase-8 as a physiological inhibitor of RIPK3-mediated necroptosis (Kaiser et al., 2011; Oberst et al., 2011).”
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Self-citationRIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
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“Strong negative regulation of the initiation of signaling for necroptosis is mediated by caspase-8 together with a caspase-like molecule, c-FLIPL (16, 27, 28), and by the ubiquitin ligases cIAP1 and cIAP2 (29).”
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“EXPERIMENTAL MODEL AND SUBJECT DETAILS Mice—Casp6—/— (Jackson Laboratory, 006236), Nlrp3—/— (Kanneganti et al., 2006a), Casp11—/— (Kayagaki et al., 2011), Gsdmd−/− (Karki et al., 2018), Nlrc4—/— (Mariathasan et al., 2004), Aim2—/— (Jones et al., 2010), Rip3−/− (Newton et al., 2004), Rip3−/−Casp-8−/− (Oberst et al., 20…”
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“Thus, similar to the requirement of caspase-8 for supporting normal embryonic development (Kaiser et al., 2011; Oberst et al., 2011; Zhang et al., 2011b), caspase-8 activity may be required to maintain normal CNS function in adult life by suppressing the activation of RIPK1 and RIPK3.”
BackgroundThe TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond
Dostert, C., Grusdat, M., Letellier, E., & Brenner, D. (2018) · Physiological Reviews · doi:10.1152/physrev.00045.2017 · Cited by 529
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“Stable knockdown: L929 cells were transduced with pSUPERretro-puromycin encoding scrambled or RIPK3 targeting short hairpins as described previously 7 .”
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Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
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“Caspase-8 inhibits RIP3 signaling, that if left unchecked causes embryonic lethality (Kaiser et al., 2011; Oberst et al., 2011).”
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“Interestingly, it turns out that there is a high degree of overlap in the molecules that regulate apoptosis and necroptosis.59 65 91e95 Under physiological conditions, TNFR ligation results in the assembly of one of the following complexes: the TNFR complex I which mediates survival functions and involves the molecule…”
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“Recently, it was demonstrated that DR triggering may also program cells to die in a caspase-independent, necrotic way (known as programmed necrosis or necroptosis).63 Necroptosis depends on the formation of a complex containing the kinases RIP1 and RIP3.”
BackgroundMitochondria and cell signalling
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“This RIPK3dependent necrosis has numerous important roles in vivo during embryonic development and in host antiviral immunity (Kaiser et al., 2011; Oberst et al., 2011; Upton et al., 2010; Zhang et al., 2011).”
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InfluentialNLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs
Sundaram, B., Nagakannan, P., Mall, R., Wang, Y., Sarkar, R., Kim, H. J., Malireddi, R. K. S., Karki, R., Janke, L. J., Vogel, P., et al. (2023) · Cell · doi:10.1016/j.cell.2023.05.005 · Cited by 443
“N/A Ripk3Casp8 mice Oberst et al.(87) N/A Ripk3Casp8Casp1 mice This paper N/A Casp7 mice Lakhani et al.”
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“While caspase-8 in complex with the FLIPL isoform is partially active and this heterodimer can inhibit necroptosis (42), elevated levels of FLIPS may suppress the activation of caspase-8 to promote necroptosis (22).”
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“zymatically inert homolog cellular FLICE-like inhibitory protein long (cFLIPL) an active complex that prevents RIPK3dependent necroptosis.(36) These data demonstrate that FADD and caspase-8, but also cFLIPL, counteract RIPK1- and RIPK3-dependent necroptosis during development.”
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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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