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Review
, 1824 (1), 113-22

Proliferative Versus Apoptotic Functions of caspase-8 Hetero or Homo: The caspase-8 Dimer Controls Cell Fate

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Review

Proliferative Versus Apoptotic Functions of caspase-8 Hetero or Homo: The caspase-8 Dimer Controls Cell Fate

Bram J van Raam et al. Biochim Biophys Acta.

Abstract

Caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. It has become increasingly clear that the heterodimer of caspase-8 with the long isoform of cellular FLIP (FLIP(L)) fulfills these pro-survival functions of caspase-8. FLIP(L), a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIP(L) heterodimer has a restricted substrate repertoire and does not induce apoptosis. In essence, caspase-8 heterodimerized with FLIP(L) prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis. This review discusses the latest insights in caspase-8 homo- versus heterodimerization and the implication this has for cellular death or survival. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

Figures

Figure 1
Figure 1. The human caspases
A: Phylogenetic tree of all the human caspases. Pro-apoptotic caspases are marked in green, pro-inflammatory caspases in red. Caspases with no clear apoptotic of inflammatory function are marked in black. Image generated with Genious Tree Builder using the full length protein sequence of the human caspases using Genious Pro v5.1.6, as developed by Biomatters Ltd. B: Over all organization of the initiator and executioner caspases. The yellow circle (●) on the ‘large’ subunit denotes the active site cysteine; blue circles (●) in the linkers denote caspase cleavage sites.
Figure 1
Figure 1. The human caspases
A: Phylogenetic tree of all the human caspases. Pro-apoptotic caspases are marked in green, pro-inflammatory caspases in red. Caspases with no clear apoptotic of inflammatory function are marked in black. Image generated with Genious Tree Builder using the full length protein sequence of the human caspases using Genious Pro v5.1.6, as developed by Biomatters Ltd. B: Over all organization of the initiator and executioner caspases. The yellow circle (●) on the ‘large’ subunit denotes the active site cysteine; blue circles (●) in the linkers denote caspase cleavage sites.
Figure 2
Figure 2. Schematic of the caspase-8 phylogeny
Two distinct caspase-8 family members arose in the chordate branch of the eukaryotes. Caspase-18 and the ancestor of -8 and -10 we call ‘caspase-810’ in this schematic, are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810. Birds and lizards express three apical caspases in the DR pathway; caspase-8, -10 and -18. Mammals subsequently lost caspase-18, while rodents lost caspase-10. See also Eckhart et al. [158].
Figure 3
Figure 3. Caspase-8 activation through homo- vs. heterodimerization
Caspase-8 (green) can either homodimerize with another molecule of caspase-8, leading to a homodimer wherein caspase-8 is fully processed and induces apoptosis (top) or heterodimerize with FLIPL (blue) to form a heterodimer wherein FLIPL is primarily processed to induce cell survival (bottom). In either case, dimerization is mediated by the adaptor protein FADD (violet).
Figure 4
Figure 4. Structural insights in caspase-8 activation
A: Structural overlay of the caspase-8 monomeric zymogen (green) and the substrate bound, fully-processed, caspase-8 dimer (orange; only one caspase-8 subunit is shown). During dimerization, a loop containing a small helix (in red) translocates from the active site (1), as indicated by the red arrow. Afterwards, the linker (blue) between the large and small subunits gets processed (2), opening up the active site completely for substrate binding. The inhibitor Z-EVD-CMK, in yellow, indicates the location of the active site cleft in the structure. B: Structural overlay of the caspase-8 homo-dimer (earth colors) versus the caspase-8/FLIPL heterodimer (blues). Over all structural changes upon formation of either the homodimer or the heterodimer are grossly similar. C-E: Comparison of the substrate cleft in the monomer (C) versus the peptide-bound homodimer (D) and the peptide-bound heterodimer (E). The substrate cleft is closed in the monomeric zymogen, whereas the cleft is accessible for substrate binding in both dimers. The synthetic peptide Ac-IETD-CHO is shown in magenta bound in the substrate cleft of the heterodimer (E). Based on PDB entries 1QDU, 2K7Z and 3H11 [53,70,88]. Images generated with PyMOL v1.4.
Figure 5
Figure 5. Progressive processing of caspase-8 determines the outcome of RIPK1-signaling
1) If caspase-8 is not activated, the complex of RIPK1 (top, orange), FADD (middle, violet) and caspase-8/FLIPL (bottom, green/blue) induces necroptosis, as indicated in the left pane of the figure. 2) Moderate caspase-8 activation in the complex results in FLIPL cleavage, possibly RIPK1 cleavage and signaling towards NF-κB. 3) Cleavage of caspase-8 inter subunit linker in the heterodimer, possibly by an external protease, results in a moderate apoptotic signal and RIPK1 cleavage. 4) Full activation and processing of caspase-8 in the homodimer results in efficient cleavage of RIPK1 and signaling towards apoptosis. Ubiquitination of both RIPK1 and caspase-8 controls the formation of the complex (not in the figure).

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