13 - Apoptosis Flashcards
Molecular classification of 2018
- intrinsic apoptosis
- extrinsic apoptosis
What is apoptosis
terminates immune response after infection, eliminates self-
reactive lymphocytes or those without functional receptors, induced by cytotoxic cells
Apoptosis vs necrosis
- apoptosis: regulated and controlled
- necrosis: cell/tissue damage, causes inflammatory response
Purpose of apoptosis
- Kills virally infected/malignant cells
- Wound healing
- Controls lifespan of immune cells
(i) natural longevity
(ii) reducing post-infection cell numbers
Apoptosis pathways
Differ in upstream events, converge on caspase activity
Caspases
Proteolytic enzymes (cysteine proteases) which cleave aspartic acid residues in target protein
Cells of apoptosis
- Single cells or small clusters of cells
- Cell shrinkage, pyknosis (chromatin condensation),karyorrhexis (nuclear fragmentation)
- Intact cell membrane, cytoplasm retained in apoptotic bodies, no inflammation
Apoptosis pathways
Extrinsic pathway OR intrinsic pathway THEN execution pathway
Extrinsic pathway
- receptor mediated
- recruitment of adaptor proteins
- activation of caspase 8
- activation of caspase 3
Intrinsic pathway
- stimulus e.g., absence of certain cell factors, presence of toxins
- Changs in membrane permeability
- release of pre-apoptotic proteins
- activation of caspase 9
Execution pathway
- cell shrinkage, chromatin begins to condense, membrane blebs form
- extensive blabbing, chromatin heavily condensed, nucleus breaking down
- formation of apoptotic bodies
Instrinic pathway in detail
- stimulus: e.g. absence of certain cell factors, presence of toxins
- pro-apoptotic proteins
- inhibit anti-apoptotic proteins e.g., Bcl-2
- [AIF, endocrine G, CAD –> nucleus (END)] OR [Smac/Diablo, Omi/HtrA2-inhibit IAPs (end)] OR [cytochrome c (cont.)]
- assembly of procaspase 9 with hepameric complex of Apaf-1 molecule
- caspase 9 activation
- activation of caspase 3
Extrinsic pathway in detail
- initiated by death receptors: members of TNF-receptor superfamily
- Receptors contain ‘death domains’ (DD) in intra-cellular region - recruitment of adaptor protein complex
- proteins also contain death domains, e.g., FADD or TRADD - death inducing signalling complex (DISC) forms
- activated caspase 8
- complex associates with procaspase 8 - caspase 9 activation
Apoptosis and disease : cell attrition caused by excessive apoptosis
NEUROGENERATIVE DISEASE:
- huntingtons disease
- SMA
INFECTION
- sepsis
- shigellosis
- AIDS
ISCHEMIA
- stroke
- myocardial infarction
HEMATOLOGICAL DISEASE:
- MDS
- cyclin neutropenia
AUTOIMMUNE DISEASE
- type I diabetes
- hashimotos thyroiditis
METABOLIC DISEASE
- Wilsons disease
-alcoholic hepatitis
Apoptosis and disease : cell accumulation caused by defective apoptosis
MALIGNANT DISEASE:
- carcinoma
- leukaemia
- lymphoma
AUTOIMMUNE DISEASE:
- SLE
- ALPS
-rheumatoid arthritis
HEMATOLOGICAL DISEASE:
- polycythemia vera
- FHL
Features of necrosis
- Triggered by interference with energy supply of cell
- Direct membrane damage
- Cell swells, cytoplasmic vacuoles form
- Distortion/disruption of organelles such as ER, mitochondria, lysosomes
- Detachment/disaggregation of ribosomes
- Rupture of cell membrane, releasing cytoplasmic content
Importance of apoptosis
- Apoptosis important in many biological processes besides immunity.
- Shows distinct cellular changes, ultimately seen as membrane bound, apoptotic vesicles, in which cell contents are safely contained.
What is apoptosis dependent on?
Apoptosis is caspase dependent, with different caspases being activated depending on whether apoptosis is extrinsic or intrinsic
What mediates extrinsic apoptosis?
Extrinsic apoptosis is receptor-mediated and involves caspase 8 and the formation of a death-induced signalling complex
What can intrinsic apoptosis result from?
Intrinsic can result from absence of certain cell signals, or presence of toxins, and is mediated by caspase 9 and formation of the apoptosome
What does caspase 3 trigger
Caspase 3 triggers the execution pathway from both the extrinsic and intrinsic pathways
