Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis

By A. Oberst, C. Dillon, R. Weinlich, L. McCormick, Patrick Fitzgerald, C. Pop, R. Hakem, G. Salvesen, Douglas R. Green. Nature, 2011

1,261 citations recorded by the source corpus.

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 (FLIPL, also known as CFLAR), and this complex is required for the protective function.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4fed756306ecb23bf00864af57fb6849ae4bfab3

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Citations in the corpus

Regulation of tumour necrosis factor signalling: live or let die (2015, background): “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 .”
Human Monocytes Engage an Alternative Inflammasome Pathway. (2016, neutral): “…FasR requires both catalytic caspase activity and auto-proteolysis, caspase-8-mediated inhibition of TNF-mediated necroptosis was shown to require catalytic caspase activity only, with a heterodimer of caspase-8:cFLIP being operational in this setting (Oberst and Green, 2011; Oberst et al., 2011).”
Cell Death Signaling. (2015, background): “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).”
Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span (2017, background): “Caspase-8 initiates apoptosis through caspase-3/7 activation and blocks necroptosis via suppression of RIPK1–RIPK3 signaling (Hutcheson and Perlman, 2008; Oberst et al., 2011).”
Caspases and their substrates (2017, background): “caspase-8 can suppress necroptosis is not fully understood, but it appears that its catalytic activity is necessary.(81)”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “Embryonic lethality of Casp8 (cid:1) / (cid:1) mice can be rescued by loss of necroptotic pathway effectors Ripk3 or Mlkl , suggesting a predominant role of apoptotic CASP8 in preventing necroptosis during development; indeed, both RIPK1 and RIPK3 are substrates for CASP8 [104– 107].”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “…critical for preventing extensive necrosis during embryonic development in order to ensure proper clonal expansion of lymphocytes and to prevent extensive necrosis and inflammation in skin and intestinal epithelium (Kaiser et al., 2011; Oberst et al., 2011; Welz et al., 2011; Zhang et al., 2011).”
Necroptosis: a regulated inflammatory mode of cell death (2018, background): “Hence, complex I is a crucial checkpoint for cell survival and necroptosis [31].”
DAI complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA (2012, positive): “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).”
Caspase functions in cell death and disease. (2013, background): “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. 201”