cFLIP suppresses caspase-1- and MLKL-independent perinatal lethality driven by auto-processing impaired caspase-8 D387A

  • Cell Death Differ. 2025 Dec 12. doi: 10.1038/s41418-025-01650-0.
Kim Newton  #  1 ,  Katherine E Wickliffe  #  2 ,  Allie Maltzman  2 ,  Debra L Dugger  2 ,  Juan Reyes Jr  3 ,  Natasha Bacarro  3 ,  Søren Warming  3 ,  Neha Rohatgi  4 ,  Rohit Reja  5 ,  Joshua D Webster  6 ,  Vishva M Dixit  2
Affiliations
  • 1. Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. [email protected].
  • 2. Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • 3. Department of Animal Genetic Technologies, Genentech, South San Francisco, CA, USA.
  • 4. Roche Informatics, Hoffman-La Roche Canada, Mississauga, ON, Canada.
  • 5. Genentech Computational Sciences, Genentech, South San Francisco, CA, USA.
  • 6. Department of Pathology, Genentech, South San Francisco, CA, USA.
  • # Contributed equally.
PMID: 41381861 DOI: 10.1038/s41418-025-01650-0
Abstract

Death ligands, including FAS ligand (FASL) and tumor necrosis factor (TNF), trigger Apoptosis by promoting Caspase-8 dimerization and activation. Impaired FAS signaling causes unconventional lymphocytes to accumulate, resulting in lymphadenopathy. Although autoprocessing of Caspase-8 is considered important for Apoptosis, autoprocessing-deficient Casp8D387A/D387A mice do not develop lymphadenopathy. We show that this is because heterodimers of Caspase-8 D387A and cFLIP, besides suppressing MLKL-driven Necroptosis, can also induce Apoptosis. Interestingly, Caspase-8 D387A elicited MLKL- and caspase-1-independent intestinal atrophy and perinatal lethality in mice lacking cFLIP. Caspase-8 D387A interacted with FADD and RIPK1 in the intestine, where there was aberrant cleavage of N4BP1 and Caspase-3, plus enhanced NF-κB signaling. Eliminating FADD, the adaptor protein that promotes Caspase-8 oligomerization, prevented this perinatal lethality. Collectively, our results suggest that cFLIP forms heterodimers with Caspase-8 D387A to promote Apoptosis in some contexts, while limiting the activity of Caspase-8 D387A homodimers in Others.

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