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APOPTOSIS

APOPTOSIS: Overall scheme

• Function: Mechanism(s) actively producing cell death
• Features: Morphologic
  • Cell shape: Rounding-up
  • Pseudopodes: Retraction
  • Cellular and nuclear volume: Reduction (Pyknosis)
  • Nuclei: Fragmentation (Karyorrhexis)
  • Cytoplasmic organelles: Minor modifications
  • Plasma membrane: Blebbing
  • Dead cell disposal (in vivo): Engulfment by resident phagocytes
• Pathways: 2 types that may overlap
  • Mitochondrial: Can be blocked by blocking cytochrome C
  • Death receptor: Stimulated by CD95, Trail, TNF & other factors
• General Causes
  • External
  • Exogenous oxidative stress: Ischemia (Mild)
  • Excitotoxins: Glutamate; Ion fluxes
  • Trophic factors: Reduced receptor occupancy
  • Stimuli: TNF-α; Corticosteroids (Lymphoid system)
  • Toxins: β-Amyloid
  • Internal
  • Toxic substances: Mutated SOD1
  • Byproducts of cell metabolism
• Cell signals
  • Cell stress
    • Mitochondrial permeability: Increased
    • Release of: Cytochrome c
  • Extracellular signal: Ligand-Receptor
• Caspase activation
  • Often important factor in apoptosis
  • Some apoptosis is caspase-independent
• Expression of "Death" genes: Reversible
• Terminal apoptotic changes: Irreversible
• External link: R&D I; II

APOPTOSIS: Related diseases & proteins

• Autoimmune lymphoproliferative syndrome
  • Tumor necrosis factor ligand superfamily, Member 6 (TNFSF6; CD95L; CD178) : Also Systemic lupus erythematosus, susceptibility
  • Tumor necrosis factor receptor superfamily, Member 6 (TNFRSF6; FAS antigen; CD95)
  • Caspase 8
    • Lymphadenopathy, splenomegaly & defective CD95-induced apoptosis of peripheral blood lymphocytes
    • Recurrent sinopulmonary & herpes simplex virus infections
    • Poor responses to immunization
    • Defects in activation of T lymphocytes, B lymphocytes, & natural killer cells leading to immunodeficiency
  • Caspase 10 (Apoptosis-related cysteine protease)
• Neoplasms
  • Tumor protein p53
    • Li-Fraumeni syndrome
    • Other neoplasms: Pancreatic; Hepatocellular; Histiocytoma; Osteosarcoma; Breast; Nasopharyngeal
  • Tumor necrosis factor receptor superfamily, Member 6 (TNFRSF6; FAS antigen; CD95) : Squamous cell
  • Tumor necrosis factor receptor superfamily, Member 10B (TNFRSF10B) : Squamous cell
  • BCL2-associated X protein (BAX) : T-Cell acute lymphoblastic leukemia; Colorectal
• Neuromuscular
  • Motor neurons: May be sensitive to apoptotic cell death
  • Congenital myopathy with apoptosis
• Mitochondrial
  • Leukodystrophy, Cavitating: APOPT1
• Mouse disorders
  • Caspase 9 : Knockout
    • Enlarged & malformed cerebrum: Caused by reduced apoptosis during brain development

DEATH PATHWAYS: APOPTOSIS vs NECROSIS
PATHOLOGICAL FEATURES
	Apoptosis	Necrosis
Patterns of death	Single cells	Groups of,   or single, cells
Cell size	Shrinkage Fragmentation	Swelling   (Oncosis)
Plasma membrane	Preserved continuity Blebbed Phosphatidylserine on surface	Smoothing Lysis: Early
Mitochondria	Increased membrane permeability Contents released into cytoplasm   Cytochrome c; Apaf1 Structure relatively preserved	Swelling Disordered structure
Organelles	Contracted "Apoptotic bodies"	Swelling; Loss Disruption
Nuclei	Chromatin:   Clumps & Fragmented	Membrane disruption
DNA degradation	Fragmented   Internucleosomal cleavage   Free 3' ends   Laddering on electrophoresis DNA appears in cytoplasm	Diffuse & Random
Cell degradation	Phagocytosis No inflammation	Inflammation Macrophage invasion
MECHANISMS
General stimuli	Developmental programs   Endogenous signals   Intercellular signals Disease processes	Disease processes
Specific stimuli	Growth factor deprivation: NGF; IL-2 Death activators: Bind to surface receptors   Cytokines: TNF-α; Lymphotoxin   Fas ligand   TRAIL Toxic: Hormones; Radiation; Ischemia, mild Oxidants in cell: Increased DNA damage	Toxic Ischemia, severe Radiation
Cellular processes	Programmed cascade of reactions   Caspase activation   Internucleosomal endonucleases   Transglutaminase activation Requires   New RNA transcription   Protein synthesis   ATP	No protein synthesis No RNA transcription Energy independent ATP depletion
Apoptosis   Inhibitors	Protease inhibitors   NAIP ; crmA; p35 ; XIAP   HIAP-1 ; IAP-2 ; IAP3 Bcl-2 family (Some)   Bcl-2 ; Mcl-1 ; Bcl-w ;   Bcl-xL EGLN3
Apoptosis   Promoters	Bcl-2 family (Some)   Bax ; Bcl-xS; Hrk ; Bak ;   Bid ; Bik ; Bad

CASPASES: Cysteine Aspartate Specific ProteASEs

General characteristics

• Highly specific proteases
• Cleave proteins exclusively after aspartate residues
• Sequence of 3 amino acids before aspartate determines substrate specificity
• Function: Regulate proteolysis during apoptotic cell death

Caspase types: Based on sequence of activation in apoptosis

• Initiator (Activator) caspases
  • First to be activated on commitment of cell to die
  • Activated initiator caspases: Cleave & activate effector caspases
  • Prodomains: Long; Contain regulatory sequences
• Effector (Executioner) caspases
  • Cleave & activate cellular substrates
  • Prodomains: Short; No known regulatory sequences
• Cytokine processors (Inflammatory)
  • Prodomains: Long; Contain regulatory sequences

Class	Name	Regulatory unit	Adapter molecule	Optimal tetrapeptide
Activators	Caspase-2	CARD	RAIDD	DXXD
	Caspase-8	DED	FADD	(I/V/L)EXD
	Caspase-9	CARD	Apaf-1	(I/V/L)EHD
	Caspase-10	DED	FADD	(I/V/L)EXD
Executioners	Caspase-3			DEXD
	Caspase-6			(I/V/L)EXD
	Caspase-7			DEXD
Cytokine processors	Caspase-1	CARD	CARDIAK	(W/Y/F)EHD
	Caspase-4	CARD		(W/Y/F)EHD
	Caspase-5			(W/Y/F)EHD
	mCaspase-11
	mCaspase-12
	Caspase-13
	mCaspase-14
CARD: Caspase recruitment domain DED: Death effector domain