Extrinsic Pathway of Apoptosis
(The Receptor-Mediated Programmed Cell Death Pathway)
In the extrinsic pathway of apoptosis, the death-inducing signal for the programmed cell death is triggered by an external stimulus. For receiving such an external death-inducing signal, the cell possesses plasma membrane receptors specific to each stimulus and thus the extrinsic signalling of apoptosis is also known as the Receptor Mediated programmed cell death pathway.
The external stimuli for the apoptosis in most of the cases will be a cytokine. The most studied cytokine to induce extrinsic pathway of apoptosis is an extracellular messenger protein called Tumor Necrosis Factor (TNF). TNF is so named because it was first discovered as a protein factor which induces cell death in cancerous cells. The TNF cytokine is produced by the cells of the immune system in response towards the adverse conditions. The adverse conditions that can provoke the immune cells to produce TNF are:
Ø Exposure to radiation
Ø Introduction of viral toxins
Ø Exposure to elevated temperature
Ø Exposure to other toxic substances
The detailed signaling mechanism of TNF-mediated extrinsic pathway of apoptosis is summarized below:
Ø TNF first binds to its receptor called TNFR1 (Tumor Necrosis Factor Receptor-1) present on the plasma membrane.
Ø TNFR1 is a member of death receptor family proteins that turn on the apoptotic cell death process in eukaryotic cells.
Ø TNFR1 is a trans-membrane receptor with an external ligand binding domain and a cytosolic domain.
Ø The TNRF1 in the plasma membrane is presented as a pre-assembled trimer.
Ø The cytosolic domain of each TNFR1 subunit contains a segment of about 70 amino acids called ‘death domain’.
Ø Binding of TNF to the TNFR1 receptor cause a conformational change in the death domain.
Ø This conformational change in the ‘death domain’ cause the recruitment of many apoptosis-related adaptor protein factors.
Ø To the activated death domain, two cytosolic adaptor proteins (TRADD and FADD) and Pro-caspase-8 residues are binds to form a multi-protein complex.
Ø The cytosolic death domain of TNFR1, TRADD and FADD interact with one another by homologous regions present on each protein.
Ø Pro-caspase-8 and FADD possess a homologous region called ‘death effector domain’.
Ø The death effector domains of both pro-caspase-8 and FADD interacts each other.
Ø Due to these interactions, the two Pro-caspase-8 molecules cleave each other to generate an active caspase-8.
Ø A single active caspase-8 contains four polypeptide segments derived from two pro-caspases.
Ø Activated caspase-8 is an initiator caspase in the extrinsic pathway of apoptosis, they activate the downstream caspases
Ø Downstream caspases are called executioner caspases (caspase-3) that carry out the self-destruction process (apoptosis) of the cell.
Another commonly observed extrinsic pathway of apoptosis in human is by the killer lymphocytes through Fas ligand and Fas protein by the mechanism given below:
Ø Killer lymphocytes can induce apoptosis by producing a protein called Fas ligand.
Ø The Fas ligand binds to its receptor called Fas on the plasma membrane of the target cell.
Ø Similar to the death domain of TNFR1, the Fas protein can recruit intracellular adapter proteins that can aggregate Pro-caspase-8 molecules.
Ø The pro-caspase-8 molecules are then activated to caspase 8 and that in turn can activate the downstream executioner caspase (caspase-3) to induce apoptosis.