Death receptors (DRs) are a group of cell surface receptors that belong to the Tumor Necrosis Factor Receptor (TNFR) superfamily. They share a cysteine-rich extracellular domain, which is relatively conserved in the TNFR superfamily. An 80-amino-acid long cysteine-rich peptide forms the death domain (DD) in the cytoplamic tail. The DRs signaling networks can be initiated by binding to their specific ligands, Tumor Necrosis Factor (TNFs), including TNF-α, FasL, TRAIL (TNF-related apoptosis inducing ligand), LTα/β and other members. Upon ligand engagement, TNFRs will change their conformation and undergo receptor oligomerization, which often leads to recruitment of adaptor proteins through interacting with their DD domains. Adaptor proteins such as FADD (Fas-associated death domain) and TRADD (TNFR-associated death domain) could further recruit downstream associated proteins to form respective complexes to induce apoptosis.
Maintaining homeostasis requires the proper balance of cell death and proliferation. Necrosis, autophagy and apoptosis represent three mechanisms to eliminate excess or damaged cells. The first, necrosis, is characterized by swelling of the nucleus and cytoplasm resulting in spilling of the cytoplasmic contents into the environment. This cytoplasmic leakage invokes a characteristic inflammatory response. In contrast, autophagy is a homeostatic mechanism employed to recycle organelles and eliminate harmful substances. It is recognizable by the formation of an intracellular double membrane enclosed vacuole known as the autophagosome, and involves Atg family proteins. It has been proposed that autophagy also plays a role in programmed cell death and the dismantling of entire cells, although the precise mechanism is not clear. Apoptosis is a tightly regulated form of programmed cell death. It is characterized by membrane blebbing, pyknotic nuclei, cleavage of the DNA between nucleosomes, and is executed by proteases known as caspases. Anoikis is a specialized form of apoptosis that is triggered when anchorage dependent cells detach from the underlying extra-cellular matrix and may involve the signaling of integrins and cadherins.
All forms of apoptosis involve the activation of caspases. These proteases, which contain a critical cysteine at the active site and cleave substrates at aspartate residues, are divided into two functional classes. One class (e.g., caspases 8-10) contains regulatory domains, which facilitate caspase oligomerization and autoactivation. Caspase-9 is activated by cytochrome c release from the mitochondria during activation of the intrinsic pathway, while caspase-8 (and caspase-10, which is found in humans but not rodents) is activated by the death receptors. These regulatory caspases cleave and activate the second class, the distal or effector caspases (e.g., caspase-3), that carry out the proteolytic events that dismantle target cells.
Two main signaling pathways, the extrinsic pathway acting via the so-called death receptors and the intrinsic pathway, acting via the mitochondria, can initiate apoptosis, ultimately activating caspases. 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.
The Fas receptor-ligand system is one of the key players in host immune cell homeostasis and cancer immunosurveillance. Fas is a cell surface receptor that is expressed on almost all nucleated mammalian cells. Fas was originally identified to play a critical role in elimination of autoreactive T lymphocytes or activated T lymphocytes after an immune response by the host immune system. FasL is mainly expressed on activated cytotoxic T lymphocytes. FasL is a type II transmembrane molecule that is also found in a soluble form released from the cell membrane through proteolytic cleavage by metalloproteinases. Deficiency of Fas or its physiological ligand FasL leads to autoimmune lymphoproliferative syndrome (ALPS) in humans, suggesting a critical role of the Fas-mediated apoptosis pathway in lymphocytes homeostasis and suppression of autoimmune diseases. ALPS patients also exhibit increased risk of both hematopoietic and non-hematopoietic cancers. These observations thus suggest that Fas functions not only in inhibition of autoimmune diseases but also in suppression of cancer development. It has since been appreciated that Fas-mediated apoptosis is also directly involved in elimination of tumor cells by tumor-specific CTLs and thereby plays a key role in immune surveillance to suppress cancer development. CTLs are key component of the host cancer immune surveillance system. To suppress target tumors, CTL use two primary effector mechanisms: one is through polarized secretion of perforin and granzymes to lyse tumor cells; the other is through direct binding of surface expressed FasL to Fas expressed on tumor cells to induce apoptosis.