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Apoptosis:
Extrinsic Pathway

BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
Introduction
 Extrinsic pathway also known as the “death receptor
pathway”.
 The extrinsic pathway begins outside the ce...
Types of Extrinsic Pathways
 Based on the triggering stimulus and nature of the
components involved two Apoptotic pathway...
Death Receptors
• Death Receptors (DRs) are Cell surface Receptors.
• They transmit Apoptotic signals initiated by specifi...
Death Receptors
• DRs (Death Receptors) belong to the superfamily of
TNFR (Tumor Necrosis Factor Receptor).
• TNFR (Tumor ...
Adapter Molecules
• FADD (Fas-Associated via Death Domain)
• TRADD (Tumor Necrosis Factor Receptor-1-Associated
Death Doma...
Death Inducing Signaling Complex
 Death Inducing Signaling Complex (DISC) formation requires
following steps:
a. FasL (ho...
Caspases
• Caspase play the central role in the transduction of
DR apoptotic signals.
• Caspases are proteins that are hig...
Cell Apoptosis
• Disc formation is followed by blockage of FADD cofactor
function by interaction with the regulator FLIP (...
Animation

BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
Execution
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After a cell receives stimulus, it undergoes organized degradation of
cellular organelles by activ...
Removal of dead cells
• The removal of dead cells by neighboring phagocytic cells has been
termed efferocytosis.
• Dying c...
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Apoptosis extrinsic mechanism

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Apoptosis extrinsic mechanism

  1. 1. Apoptosis: Extrinsic Pathway BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  2. 2. Introduction  Extrinsic pathway also known as the “death receptor pathway”.  The extrinsic pathway begins outside the cell through activation of pro-apoptotic receptors on the cell surface.  The pro-apoptotic receptors are activated by molecules known as pro-apoptotic ligands.  Ligand binding causes receptors to cluster and ultimately form a death-inducing signaling complex (DISC).  Upon DISC activation, the extrinsic pathway has been seen to adopt the same effector caspase machinery as the intrinsic pathway BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  3. 3. Types of Extrinsic Pathways  Based on the triggering stimulus and nature of the components involved two Apoptotic pathways can be differentiated:  One involving Receptor Systems  Second triggered by Cytotoxic Stress  Receptor mediated pathways include those activated by Death ligands.  Stress effects that can induce Apoptosis are Gamma- and UV radiation, treatment with cytotoxic drugs such as Actinomycin D. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  4. 4. Death Receptors • Death Receptors (DRs) are Cell surface Receptors. • They transmit Apoptotic signals initiated by specific ligands. • Play a central role in instructive Apoptosis. • Death receptors (DRs) activate Death Caspases within seconds of ligand binding, causing an Apoptotic demise of the cell within hours. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  5. 5. Death Receptors • DRs (Death Receptors) belong to the superfamily of TNFR (Tumor Necrosis Factor Receptor). • TNFR (Tumor Necrosis Factor Receptor) are characterized by a Cys-rich Extracellular Domain. • These have a homologous Intracellular Domain known as the Death Domain. • The Fas receptor binds the Fas ligand (FasL), a transmembrane protein part of the TNF family. The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the FADD, caspase-8 and caspase-10. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  6. 6. Adapter Molecules • FADD (Fas-Associated via Death Domain) • TRADD (Tumor Necrosis Factor Receptor-1-Associated Death Domain) or Daxx • The Adapter-molecules contain Death Domains so that they can interact with the DRs and transmit the Apoptotic signal to the death-machinery. The best-characterized Death Receptors are Fas and TNFR1 (Tumor Necrosis Factor Receptor-1). BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  7. 7. Death Inducing Signaling Complex  Death Inducing Signaling Complex (DISC) formation requires following steps: a. FasL (homotrimeric protein) acts as ligand for Fas causing oligomerization of its Receptor on binding. b. Clustering of the Death Domains and binding of cofactor FADD. c. Binding of FADD protein via its DED (Death Effector Domain) motif to a homologous motif in Procaspase8. Complex of Fas, FADD and ProCaspase8 is called the DISC BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  8. 8. Caspases • Caspase play the central role in the transduction of DR apoptotic signals. • Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. • There are two types of caspases: • • initiator caspases, caspase 8,10,9,2, and effector caspases, caspase 3,7,6. • The activation of initiator caspases requires binding to specific oligomeric adaptor protein. • Effector caspases are then activated by these active initiator caspases. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  9. 9. Cell Apoptosis • Disc formation is followed by blockage of FADD cofactor function by interaction with the regulator FLIP (FLICE Inhibitory Protein). • Recruitment by FADD • Procaspase8 oligomerization • FADD activation through self-cleavage of oligomerized Procaspase8. • Activation of downstream Caspases (Caspase3 and 7) by activated Caspase8 committing the cell to Apoptosis. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  10. 10. Animation BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  11. 11. Execution • • • • • • After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated caspases. A cell undergoing apoptosis shows a characteristic morphology: Cell shrinkage and rounding are shown because of the breakdown of the proteinaceous cytoskeleton by caspases. The cytoplasm appears dense, and the organelles appear tightly packed. Chromatin undergoes condensation into compact patches against the nuclear envelope (also known as the perinuclear envelope) in a process known as pyknosis, a hallmark of apoptosis. The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as karyorrhexis. The nucleus breaks into several discrete chromatin bodies ornucleosomal units due to the degradation of DNA. The cell membrane shows irregular buds known as blebs. The cell breaks apart into several vesicles called apoptotic bodies, which are then phagocytosed. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956
  12. 12. Removal of dead cells • The removal of dead cells by neighboring phagocytic cells has been termed efferocytosis. • Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface. • Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase. • These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages. • Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. • The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. BITS Pilani, Deemed to be University under Section 3 of UGC Act, 1956

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