Question

Knowing that FAS death receptor was activated in cholesterol depleted cancer cells. Explain how activation of this receptor activates killer caspases. Explain all downstream events after activation of death receptor and stopping with how activation of execution caspases occurs.

Answer 1

FAS is the member of TNF alpha superfamily which when binds to FAS Ligand present on Tc cells and Natural killer cell induces apoptosis. It has also been found that the activity of FAS is not only regulated by FAS Ligand but also by the association of FAS to the cholesterol-rich domain (lipid raft) of the plasma membrane. When lipid raft is disrupted by using cholesterol depleting agent like beta-methyl- cyclodextrin, filipin it causes spontaneous clustering of FAS in non-lipid raft region which triggers the activation of apoptosis. When FAS binds to its ligand it causes recruitment of adaptor protein called Fas Associated Death Domain (FADD), followed by the recruitment of procaspase-8. FADD has 2 domains one bind to the FAS receptor while other binds to procaspase-8 result in proteolytic cleavage of procaspase-8 into active caspase-8. Active caspase-8 cleaves procaspase-3 and convert it into active caspase-3. once activated caspase-3 catalyzes the cleavage of many key cellulars proteins which leads to apoptosis.