Apoptosis receptors are also named death receptors (DR). Two main signaling pathways of apoptosis, the extrinsic pathway acting via the so-called death receptors and the intrinsic pathway, acting via the mitochondria, can initiate apoptosis, ultimately activating caspases.
The Bcl2 (B-cell lymphoma 2) family of proteins plays a major role in the mitochondrial driven apoptotic program. This family of proteins consists of both pro-apoptotic and anti-apoptotic members. Two of the anti-apoptotic proteins are Bcl2 and Bcl-XL (B-cell lymphoma-extra large), while the pro-apoptotic members include BID (BH3 (Bcl2 homology domain 3) interacting domain death agonist) and BAD, (Bcl2-associated death promoter) among others.
Once activated, the pro-apoptotic Bcl2 family members function by forming pores in the mitochondrial membrane facilitating the release of cytochrome c and the formation of the apoptosome. This complex contains cytochrome c, APAF1 (apoptosis protease activating factor 1) and caspase-9; its formation facilitates the oligomerization and subsequent activation of caspase-9, which can cleave and activate distal caspases.
IAPs (inhibitor of apoptosis) can block this process. These proteins (e.g., cIAP 1, cIAP 2, and XIAP (X-linked IAP)) are able to bind to and directly inhibit caspases 3, 7 and 9. IAPs also function as E3 ubiquitin ligases that are capable of auto-ubiquitination. Specifically, interaction with the mitochondrial protein SMAC (second mitochondria-derived activator of caspase) induces auto-ubiquitination and subsequent degradation of IAPs. In this way, SMAC is able to overcome the apoptotic inhibition of the IAPs.
Fig.1 Death Receptor Signaling.
Extrinsic apoptosis occurs via the death receptors. Three members of the tumor necrosis factor (TNF) superfamily of cytokines (TNF, FasL (Fas ligand), TRAIL (TNF related apoptosis inducing ligand)) are known to induce apoptosis via their cognate receptors. These three so-called death ligands initiate death receptor (DR) signaling by binding to and trimerizing their respective receptors. All three ligands are synthesized in a trans-membrane form and can function while bound to the membrane or following proteolytic cleavage of the extracellular domain (shedding) from the membrane. Once the pathway is activated, caspase-8 (as noted, in humans caspase-10 might also function similarly) cleaves distal caspases (e.g., caspase-3) leading to the molecular (e.g., DNA cleavage) and morphological (e.g., nuclear pyknosis, membrane blebbing) changes characteristic of apoptosis. In addition to directly cleaving and activating caspase-3, activated caspase-8 can also trigger the mitochondrial death pathway via BID cleavage. Cleaved (activated) BID forms pores in the mitochondrial membrane, which facilitates the release of cytochrome c and formation of the apoptosome.
Fig. 2 Summary of Death Receptors and Ligands.