Functions of caspase 8: the identified and the mysterious

Abstract

Initially discovered as an initiator protease in apoptosis mediated by death receptors, caspase-8 is now known to have an apparently confounding opposing effect in securing cell survival. It is required to allow mouse embryo survival, and the survival of hematopoietic cells during their development and activation. Classic models in which caspase-8 is depleted or inhibited frequently result in inhibition of apoptosis, and conversion to death through a necrotic pathway. This bewildering switch is now known to be driven by activation of a pathway dependent on protein kinases of the RIP family, which engage a pathway known as necroptosis. If caspase-8 does not control this pathway, necrotic death results. The pro-apoptotic and pro-survival functions of caspase-8 are regulated by a specific interaction with the pseudo-caspase cFLIP, and it is thought that the heterocomplex between these two partners alters the substrate specificity of caspase-8 in favor of inactivating components of the RIP kinase pathway. The description of how caspase-8 and cFLIP coordinate the switch between apoptosis and survival is just beginning. The mechanism is not known, the differential targets are not known, and the reason of why an apoptotic initiator has been co-opted as a critical survival factor is only guessed at. Elucidating these unknowns will be important in understanding mechanisms and possible therapeutic targets in autoimmune, inflammatory, and metastatic diseases.

Keywords: Apoptosis; Autophagy; Necroptosis; Necrosis.

Figure 1. Extrinsic and Intrinsic Apoptosis Pathways

Extrinsic and intrinsic signals regulating apoptosis had been proposed in descriptive terms [12], and later revised to cover mechanistic events, such that death mediated by death receptors (DRs) became known as the extrinsic apoptosis pathway, and death mediated through mitochondria became the intrinsic apoptosis pathway [13]. The pathways activate distinct apical caspases (casp8 and 10 in the extrinsic pathway and casp9 in the intrinsic pathway), which converge on the activation of executioner caspases 3 and 7, leading to cleavage of an unknown number of proteins to express the apoptotic phenotype.

Figure 2. Pathways Emerging from TNFR1

Upon ligation of TNFR1 three pathways emerge to program different cell outcomes. NK-κB activation is triggered through the IKK complex, and depending on the concentration of available adaptors, a separate complex that recruits components of the DISC is engaged (Complex 1). Complex 2 is considered to be the main functional apoptotic protein cluster, but it is likely that a continuous range of adaptor and effector recruitments evolves, with complex 1 and complex 2 as the extremes. The Necrosome [19], synonymous with the Ripoptosome [20, 21], is engaged. The outcome of apoptosis versus necroptosis is controlled by casp8 and cFLIP.

Figure 3. Caspase 8 and cFLIP phylogeny

Distinct family members related to modern casp8 arose in the chordate branch of the eukaryotes. A) Caspase 18 and the ancestor of caspases 8 and 10 (which we call “caspase 810” in this schematic, are still found in modern fishes. Later on in evolution, caspase 8 and 10 likely branched 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 both caspase 10 and 18, leaving them with a single apical caspase of the extrinsic pathway. cFLIP is maintained throughout the lineage. See also Eckhart et al. [52]. B) Human casp8 (red) aligned with cFLIP paralogs. In the case of cFLIP, the conservation of mutated active site residues is sustained from fish to mammals (green highlight), as is the conservation of the cleavage site between the large and small subunits (yellow highlight). Each representative species seems to have only one cFLIP paralog, with the exception of the Japanese pufferfish that has two (but not surprising given the duplication of the pufferfish genome).