TRAIL-activated apoptotic signaling pathway

Definition

Target type: biologicalprocess

An extrinsic apoptotic signaling pathway initiated by the binding of the ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) to a death receptor on the cell surface. [GOC:bf, GOC:PARL, PMID:21785459]

TRAIL (TNF-related apoptosis-inducing ligand) is a type II transmembrane protein belonging to the TNF superfamily. It plays a crucial role in regulating apoptosis, a programmed cell death process essential for maintaining tissue homeostasis and eliminating damaged or unwanted cells. When TRAIL binds to its death receptors (DR4/TRAIL-R1 and DR5/TRAIL-R2) on the surface of target cells, it initiates a cascade of molecular events leading to apoptosis.

Upon TRAIL binding, the death receptors trimerize, bringing together their intracellular death domains. This assembly recruits the adaptor protein FADD (Fas-associated protein with death domain), which also contains a death domain. FADD, in turn, interacts with procaspase-8, a proenzyme form of caspase-8, through its DED (death effector domain). This interaction forms a DISC (death-inducing signaling complex), a multiprotein platform that activates caspase-8.

Caspase-8 is a key initiator caspase in the TRAIL-mediated apoptotic pathway. Upon activation within the DISC, caspase-8 cleaves and activates downstream effector caspases, primarily caspase-3 and caspase-7. These effector caspases then cleave and activate a variety of cellular substrates, including proteins involved in DNA repair, cytoskeletal integrity, and nuclear envelope breakdown.

The activation of effector caspases ultimately leads to the dismantling of the cell through a series of events:

- **DNA fragmentation:** Caspase-activated DNases (CADs) are released from their inactive form, leading to the cleavage of nuclear DNA into fragments.
- **Cell shrinkage:** Caspases target proteins involved in cytoskeletal integrity, leading to cell shrinkage and membrane blebbing.
- **Apoptotic body formation:** The cell breaks down into apoptotic bodies, small membrane-enclosed fragments containing cellular debris, which are then engulfed by phagocytes.

The TRAIL-activated apoptotic signaling pathway is a tightly regulated process, and several mechanisms exist to prevent its inappropriate activation. These include:

- **Cellular inhibitors of apoptosis (IAPs):** IAPs are a family of proteins that bind to and inhibit caspases, preventing their activation.
- **FLIP (FLICE-inhibitory protein):** FLIP is a protein that resembles procaspase-8 but lacks caspase activity. FLIP can bind to FADD and compete with procaspase-8 for recruitment to the DISC, thereby inhibiting caspase-8 activation.
- **TRAIL decoy receptors:** TRAIL decoy receptors (TRAIL-R3/DcR1 and TRAIL-R4/DcR2) are membrane proteins that bind TRAIL but lack a death domain, preventing the formation of the DISC and downstream apoptotic signaling.

The TRAIL apoptotic pathway is involved in various physiological processes, including:

- **Immune surveillance:** TRAIL eliminates tumor cells and virally infected cells, contributing to immune system defense.
- **Development:** TRAIL is involved in the development and differentiation of tissues and organs.
- **Tissue homeostasis:** TRAIL removes damaged or unwanted cells, maintaining tissue health.

Dysregulation of the TRAIL apoptotic pathway can contribute to various diseases, including:

- **Cancer:** Some cancer cells evade apoptosis by overexpressing anti-apoptotic proteins or downregulating TRAIL receptors, leading to uncontrolled growth and metastasis.
- **Autoimmune diseases:** Overactive TRAIL signaling can contribute to the destruction of healthy cells in autoimmune diseases.

The TRAIL apoptotic pathway is a complex and highly regulated process that plays a crucial role in maintaining cellular homeostasis and protecting against disease. Understanding this pathway provides insights into the development of new therapeutic strategies targeting apoptosis for the treatment of cancer and other diseases.'
"

Proteins (1)

Compounds (16)