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Mechanisms of cell death - Coggle Diagram
Mechanisms of cell death
Apoptosis
Programmed cell death
Key cellular morphology
Chromatin condensation
Cell shrinkage
Membrane blebbing
Apoptotic bodies
Phagocytosis of apoptotic cell
DNA degradation
Phosphatidyl serine (PS)
'Eat me' signal for phagocytic cells
Flips from internal to external side of membrane
Major steps are highly conserved across species
C.elegans
is used to study apoptosis
Defined cell lineage
959 cells in adult
131 lost via apoptosis during development
Randomly mutate DNA in worms + identify genes important in apoptosis
Caspases
Cysteine-dependent aspartate-specific protease
Inactive proenzyme in normal cells
Conserved cysteine in active site
Cleave multiple proteins at specfic Asp residues
Generally target 2 groups of proteins
Cell structure proteins
Pro-survival proteins
Inactive pro-caspase
Dimersation + cleavage e.g. by a caspase
Active caspase
Initiators
Activate apoptotic cell death pathway
Inactive monomers in healthy cells
Activated by binding to protein complex + dimerisation
May also be cleaved
Not always necessary
Effectors
Cause cellular changes associated with apoptosis
Inactive dimers in healthy cells
Activated by cleavage
By initiator caspases + other effector caspases
Responsible for targeted destruction of cell + apoptotic morphology
Cytoskeleton destruction
DNA degradation
Extrinsic pathway
'Death receptor' apoptosis
Development + immune response
Removal of infected/tumourigenic cells
Stimulated by extracellular signals (often paracrine)
TNF family of cytokines
Ligand may be soluble or membrane-bound (TNF)
FAS-L is membrane only (soluble form is not active)
Receptor binding activates intracellular signalling pathway
Ligands bind to death receptor
Amplified by engaging intrinsic pathway
Ligand binds to death receptor on extracellular region
Binding of receptor causes clustering
Adaptor proteins bind to intracellular region via death domains
Pro-caspase 8 is recruited via death effector domains
Death inducing signalling complex (DISC) formation
Dimerisation/autoproteolytic cleavage of procaspase-8
Caspase-8 cleaves + activates executioner caspases
Adaptor proteins e.g. FADD - Fas associated death domain protein + TRADD, trail 'ADD'
Ligands e.g. FasL, TNF-\(\alpha\), TRAIL
TRAIL = TNF-related apoptosis-inducing ligand
Death receptor e.g. Fas, TNFR1, DR5
Intrinsic pathway
Mitochondrial apoptosis
Independent of death receptor activation
Response to cellular stress e.g. DNA/mitochondrial damage
Formation of apoptosome (equivalent of DISC)
Release of CytC from mitochondria
Promotes formation of heptameric complex of apoptotic protease activating factor-1 (APAF-1)
Binds and activates procaspase-9
Caspase-9 cleaves + activates effector caspases
Controlled by Bcl-2 protein family
Pro-apoptotic Bax/Bak promote CytC release
ATP also released for casp-9 activity
Bax monomers exist in cytosol
Oligomerise forming a CytC pore in mitochondrial membrane
Bcl-2 protein is an oncogene
Prevents apoptosis in tumour cells
Binds Bax, prevent oligomerisation
Over-expression promotes or inhibits apoptosis
BH3-only proteins activate pro-apoptotic prteins and neutralise anti-apoptotic proteins
e.g. block binding of Bcl-2 to Bax
Regulated at transcriptional and post-transcriptional levels
Phosphorylation
Intrinsic signals
Hypoxia
Nutrient withdrawal
ROS
DNA damage
Heat
Apoptosis-inducing factor-1 (AIF-1) enters nucleus + causes chromatin condensation/degradation
Amplification of pathway
Effector caspases bind Bid forming truncated Bid (tBid)
tBid activates Bax
Bid connects intrinsic + extrinsic pathways
Caspase-8 activated in extrinsic pathway can cleave Bid