Answered: How does the Apoptosis Through Death…

11th Edition

ISBN:9780134580999

Author:Elaine N. Marieb, Katja N. Hoehn

Publisher:Elaine N. Marieb, Katja N. Hoehn

Chapter1: The Human Body: An Orientation

Section: Chapter Questions

Problem 1RQ: The correct sequence of levels forming the structural hierarchy is A. (a) organ, organ system,...

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Question

How does the Apoptosis Through Death Receptors pathway work, where it works and why it works. Include a diagram of the steps.

Expert Solution

Step 1

Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the “death domain” that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10.
They initiate multiple signaling pathways, number of nonapoptosis-related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities.
Death receptors are cell surface receptors belonging to the tumor necrosis factor (TNF) superfamily, which trigger apoptosis upon ligand binding.
The best characterised death receptors are Fas , TNF receptor , TRAMP , TRAIL-R1 and TRAIL-R2 .
Fas Ligand (CD95 ligand) binds Fas, TNF and lymphotoxin a bind to TNFR1 , TWEAK binds to TRAMP and TRAIL is the ligand for both TRAIL-R1 and TRAIL-R2

Death receptors contain an intracellular death domain , which upon ligand binding associates with an adaptor protein called Fas-associated death domain (FADD) directly or indirectly via TNFR-associated death domain (TRADD)
FADD also interacts with procaspase-8 to form a complex at the receptor called the death-inducing signaling complex (DISC).
Once assembled, DISC induces the activation of caspase-8, which in turn precipitates the activation of downstream effector caspases. The BH3 only protein Bid is cleaved by pro-caspase 8 and translocates to the mitochondria to activate the intrinsic pathway , thereby linking the two death pathways.

In addition to death receptors, the TNF superfamily comprises decoy receptors (DcR), which inhibit death signaling through the sequestration of ligand. Decoy receptors include DcR1, DcR2 and osteoprotegerin (OPG), which bind to TRAIL and DcR3, which binds Fas ligand .
Death receptor signaling is also regulated by cellular FLICE-like inhibitory protein (c-FLIP) an endogenous inhibitor that interacts with FADD to antagonize apoptosis .