Apoptosis

Induction of Apoptosis:

Death receptor pathway: binding of ligand to death receptor forms a Death-Inducing Signalling Complex (DISC) comprising death receptor, ligand, and adaptor proteins such as FADD (Fas-Associated Death Domain). Apoptosis induced by the death receptors Fas and TNFR-1 proceeds through recruitment of FADD and caspase-8 to the receptor complex.

DR family

Ligand for death receptor (DR)

CD95 (Apo-1 or Fas)

CD-95L

TNF-R (tumour necrosis factor) – TNFR1-induced apoptosis (in contrast to Fas) is a two-step process, mediated by two sequential signaling complexes

TNFα

Binding of TNF to TNFR1 leads to rapid recruitment of TRADD, RIP1 and TRAF2. Subsequently, TNFR1, TRADD and RIP1 are modified and dissociate from TNFR1. The liberated death domain (DD) of TRADD (and/or RIP1) binds to FADD, leading to recruitment of caspase-8/10 recruitment (forming complex II) and resulting in apoptosis. [s]

Mitochondrial pathway:

Bcl-2 regulators of mitochondrial permeability:

Bcl-2 subfamily (Bcl-2, Bcl-xL and Bcl-w) anti-apoptotic, promote cell survival. BH1-BH4.

Bax subfamily (Bax, Bak, BAD) pro-apoptotic, promote cell death. Sequence homology with BH1, BH2, and BH3 regions of Bcl-2.

BH3 only subfamily (Bid) pro-apoptotic, promotes cell death. Sequence homology only in BH3 region. Bid lacks the transmembrane-spanning region.

Pro-apoptic substances (leak through PT pore comprising ANT, PBR (MBR), and VDAC (porin):

AIF - Apoptosis Inducing Factor – flavoprotein that fragments DNA.

Endonuclease G – degrades single stranded DNA.

Smac/DIABLO - Second Mitochondrial Activator of Caspases/Direct IAP Binding protein with Low pI – pro-aptoptic activity through inhibition of IAPs (Inhibitors of Apoptosis Proteins), which are inhibitors of caspases (3, 8).

Cytochrome c – component of oxidative phosporylation that drives generation of apoptotic body (apoptosome).

Components of PT pore (Mitochondrial Permeability Transition Pore):

ANT Adenine Nucleotide Transporter – adenine nucleotide transporter of inner mitochondrial membrane.
PBR (MBR) Mitochonrial or Peripheral Benzodiazepine Receptor – outer mitochondrial membrane.
VDAC Voltage Dependent Anion Channel – outer mitochondrial membrane.

Apoptotic events:

Caspase function: cysteinyl aspartate-specific proteases that that cleave proteins at aspartate residues, leading to activation (caspases, ICAD) or deactivation ( PARP-1, PKB/Akt, Raf-1). Pro-apoptotic caspases are generally activated by death-receptors or damaged mitochondria and are inhibited by a number of cytoplasmic proteins including the caspase-8 homologue FLIP. Modulators of caspase activation are aberrantly expressed in pathological processes such as neurodegenerative diseases or cancer. [s]

Initiator caspases Activated by autoactivation. Caspase-8 and caspase-9 activate effector caspases.
Effector caspases Transactivated by initiator caspases. Caspase cascade leads to protein cleavage, ultimately leading to apoptotic cell death.
Inflammatory caspases Inflammatory caspase-1 and caspase-5 are involved in the proteolytic activation of IL-1β, which activates the rapidly acting innate immune system. They are activated by a multiprotein complex, the inflammasome.[s]

Caspase actions:

Site

Action

Nuclear pores Active caspase-9 damages/enlarges nuclear pores, permitting entry of caspase-3 and caspase-7
Nucleus Caspase-3 cleaves the inhibitory subunit of ICAD, releasing CAD, which cleaves DNA between nucleosomes. ICAD is an inactive protein-CAD complex (45kDa), where CAD is Caspase-Activated DNase (DNA Fragmentation Factor, 40kDa)
Plasma membrane Externalization of phospholipid, phosphatidyl-serine from inner to outer plasma membrane signals for phagocytosis after phagocytes adhere (CD14).
Cytoskeleton Reorganization of cytoskeleton and disintegration into apoptosomes.

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