Mechanisms of Apoptosis

Caspases, which carry out a series of cleavage events that signal for apoptosis, can be categorized into initiator and executioner caspases. When inactive, caspases are called procaspases. Initiator caspases are activated by dimerization, which is driven by several pathways described below. Dimerized initiator caspases will cleave and activate executioner caspases. Executioner caspases then go on to cleave a number of substrates, including cytoskeletal components, membrane proteins, and endonucleases, resulting in DNA destruction and cell death.

 

Caspase Activation Pathways

 

Extrinsic pathway

 

The extrinsic pathway is regulated by signaling through receptors of the Tumor Necrosis Factor receptor (TNFR) superfamily. These receptors include TNFR, Fas, and TNF-related apoptosis inducing ligand (TRAIL) receptors. Binding of a ligand to its respective receptor activates adaptor proteins that contain death domains, such as FADD and TRADD. Adaptor proteins recruit and facilitate the dimerization of initiator caspases like caspase 8 and 10, which are assembled at the death inducing signaling complex (DISC). This pathway can be negatively regulated by decoy TRAIL receptors (TRAIL R3 and R4) which compete for TRAIL binding. 

 

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Intrinsic pathway

 

The intrinsic pathway is triggered by detection of cellular stresses, such as DNA damage and hypoxia, or by the absence of signaling from growth factors, hormones, and cytokines. This results in the increased permeability of the mitochondrial membrane, which is regulated by pro- and anti-apoptotic members of the Bcl-2 family (e.g. Bax, Bak, Bad). Cytochrome c is then released from mitochondria to activate adapter protein apoptotic protease-activating factor-1 (APAF1), which forms the apoptosome with dimerized initiator caspase 9. Extrinsic pathway signaling can also cross-activate mitochondrial release of cytochrome c through caspase 8-mediated cleavage of Bid, a pro-apoptotic member of the Bcl-2 family.

 

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Granzyme pathway

 

Cytotoxic CD8+ T lymphocytes (CTLs) and natural killer (NK) cells can kill target cells (e.g. cancer cells, infected cells) through FasL/Fas binding, and through secretion of granules containing proteases granzyme A and B. These granules penetrate the target cell membrane through pores formed by perforin. FasL/Fas interaction can trigger extrinsic apoptosis, and is the primary killing mechanism used by NKT cells, a subset of T cells that recognize CD1d. Granzyme B can directly cleave and activate initiator and executioner caspases. Granzyme B can also cleave Bid to induce cytochrome c release and the intrinsic apoptotic pathway. In contrast, granzyme A induces cell death through mechanisms independent of caspases.

 

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Caspase Description

Caspase 1

Inflammatory caspase that cleaves pro-IL-1β to generate the active cytokine

Caspase 3

The major executioner caspase that can be activated by any of the initiator caspases (8, 9, 10)

Caspase 7

Executioner caspase that can be cleaved by granzyme B and caspases 3, 9, and 10

Caspase 8

Initiator caspase activated by FasL/Fas signaling

Caspase 9

Initiator caspase activated by the apoptosome and intrinsic pathway

Caspase 11

Inflammatory caspase activated by LPS or TLR sensing

References:

 

  • Portt et al. Anti-apoptosis and cell survival: A review. Biochimica et Biophysica Acta (2011). PMID: 20969895
  • McIlwain et al. Caspase Functions in Cell Death and Disease. Cold Spring Harb Perspect Biol (2013). PMID: 23545416
  • Pinkoski et al. Granzyme B-mediated Apoptosis Proceeds Predominantly through a Bcl-2-inhibitable Mitochondrial Pathway. J Biol Chem (2001). PMID: 11278459
  • Elmore. Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol (2007). PMID: 17562483
  • Hagar et al. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science (2013). PMID: 24031018
  • Galluzzi et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ (2018). PMID: 29362479
  • Krijgsman et al. The Role of Natural Killer T Cells in Cancer – A Phenotypical and Functional Approach. Front Immunol (2018). PMID: 29535734
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