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cell death
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Lecture notes of 9 pages for the course Mechanisms of pathology at Aston (immunology notes)
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Cell death.Revision on apoptosis.
Programmed cell death (often apoptosis) is part of normal organism development,
for example in moulding structures and tissues of the body.
It is also used in the immune system to prevent self-immunity, such as in the clonal
deletion of autoreactive T-cells.
However, it can also occur during cell stress, for example when DNA damage is too
severe to repair.
PCD is also important in clearing neutrophils that have ingested bacteria during
immune reactions.
Pathways of apoptosis.
Apoptosis is a complex process involving many components.
There are 2 main pathways for initiation of apoptosis.
Extrinsic pathway: death receptor ->effector caspases->apoptosis.
Intrinsic pathway: mitochondria->effector caspases->apoptosis.
The extrinsic pathway.
A set of specialised death signals are received by death receptors on the cell surface.
All the receptors have death domains.
Ligand binding induces the formation of a death inducing signalling complex (DISC)
Adaptor proteins (e.g. FADD) are recruited. FADD= fas-associated death domain.
These recruit procaspase-8 and activate it by proteolytic cleavage.
The extrinsic pathway can involve cell-cell or ligand-cell interactions.
Cytotoxic T cells use the cell-cell mechanism to induce apoptosis in target cells, such
as infected or cancerous cells.
Several soluble ligands of death receptors also exist.
The intrinsic pathway.
The intrinsic pathway can be activated by mnay varied stresses and treatments
(including oxidative stress).
All signals seem to converge on the mitochondria and cause mitochondrial outer
membrane permeabilization (MOMP).
There are 2 models for how this happens:
Pore formation by pro-apoptotic proteins Bax and Bak.
Induction of the mitochondrial permeability transition (MPT) by formation of a
permeability transition pore (PTP).
Events in the intrinsic pathway.
MOMP allows release of mitochondrial proteins, e.g. cytochrome C.
Cytochrome c interacts with & polymerizes apaf-1 (apoptotic protease-activating
factor-1).
Procaspase-9 joins the complex to form the apoptosome, and is activated.
, Caspase-9 catalyses the activation of the executioner caspase cascade by proteolytic
cleavages.
Other digestive proteins are also released, e.g. endonuclease G.
The caspases: initiators and executioners
Caspases are normally only activated following induction by death receptors or the
apoptosome.
Caspases 3,6 &7 are executioner caspases. Both pathways converge on caspases 3 &
6.
Downstream apoptotic events and cell ‘execution’
Caspases are central in controlling and effecting apoptosis.
Caspases cause apoptosis by destroying several critical enzymes and proteins.
Apoptosis can be induced by stress-related signalling.
Apoptosis can be beneficial or deleterious: diseases can be caused by excess
apoptosis or lack of it.
The caspases: initiators and executioners.
Caspases are normally only activated following induction by death receptors or the
apoptosome.
Caspases 3,6 &7 are executioner caspases. Both pathways converge on caspases
3&6.
Caspases: cysteine aspartate proteases.
Caspases are responsible for cleavage of key proteins seen at onset of apoptosis.
Caspases mediate disassembly of cells via proteolysis, which is irreversible.
Inhibition of caspases inhibits apoptosis (evidence for their role).
Post-translational activation correlates with onset of apoptosis.
Caspases are synthesised as precursors capable of auto-regulation and activation, in
order to prevent inappropriate damage to the cell.
The reactions are highly specific, which helps to ensure selective protein
degradation.
They cleave after aspartate, XXXXD, where XXXX depends on enzyme. (e.e. DEVD for
caspase-3).
Caspase structure and activation.
1. Caspases are constitutively present.
2. Cleavage of the zymogen activates the enzyme.
3. The active enzyme can initiate a cascade.
4. Apoptosis can be initiated in 30 minutes.
5. Effective regulation is essential otherwise unnecessary damage would occur.
The active site in caspase-3 has a cysteine-histidine dyad, cys163 and His 121. The cysteine is
nucleophilic and attacks the peptide bond next to Asp in the substrate’s cleavage site.
Downstream actions and effects.
Caspases cause DNA degredation and nuclear condensation.
Inactivation of DNA repair and replication enzymes.
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