Caspases

The  inflammasome, is responsible for caspase-1 activation, the intracellular cysteine proteases that cleave substrates after aspartate residues and play integral roles in apoptosis 

 

Caspases are classified as proinflammatory or proapoptotic, depending upon the cellular processes in which they are involved. 

The role of these enzymes in programmed cell death, with their functions in apoptosis well characterized.

Programmed cell death, occurs widely during development, and throughout life to maintain cell homeostasis.

Caspase activation ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues.

Caspases have other roles in programmed cell death such as pyroptosis and necroptosis.

These forms of cell death protect an organism from stress signals and pathogenic attack.

They directly processes pro-inflammatory cytokines such as pro-IL1β, that allow recruitment of immune cells to an infected cell or tissue.

Other identified roles, as cell proliferation, tumor suppression, cell differentiation, neural development and axon guidance and ageing.

Its deficiency has been identified as a cause of tumor development.

There are two types of caspases: initiators and effectors.

Initiator caspases cleave inactive forms of effector caspases.

This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation.

Tumor growth can occur by factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptopic proteins such as Caspases respond by inducing cell death in abnormally growing cells.

Over-activation of some caspases such as caspase-3 can lead to excessive programmed cell death, as is seen in several neurodegenerative diseases where neural cells are lost, such as Alzheimer’s disease.

Impaired activation of caspases can increased susceptibility to infection, as an appropriate immune response may not be activated.

Inflammatory caspase-1 has been implicated in causing autoimmune diseases; drugs blocking the activation of Caspase-1 have been used to improve the health of patients.

Caspases are also used as cancer therapy.

The caspases enzymes are sub classified into three types: Initiator, Executioner and Inflammatory.

Caspases are synthesised as inactive zymogens and are only activated following an appropriate stimulus.

Activation involves dimerization and often oligomerisation of pro-caspases.

Some activating multiprotein complexes includes: The death-inducing signaling complex (DISC) of extrinsic apoptosis, intrinsic apoptosis and pyroptosis.

Apoptosis is a form of programmed cell death where the cell undergoes morphological changes, to minimize its effect on surrounding cells to avoid inducing an immune response.

Apoptopic caspases are subcategorised as:

Initiator Caspases

Executioner Caspases

Initiator caspases that are activated, produce a chain reaction, activating several other executioner caspases.

Executioner caspases degrade over 600 cellular components to induce changes for apoptosis.

Pyroptosis is a form of programmed cell death that induces an immune response.

Pyroptosis is a response to stimuli that include microbial infections as well as myocardial infarctions.

Caspase-1, Caspase-4 and Caspase-5 play important roles in inducing cell death by pyroptosis.

The proinflammatory caspases include caspases 1, 4, and 5 in humans.

 

Caspase-1, also known as ICE (interleukin-1 beta converting enzyme), is responsible for the cleavage of prointerleukin-1, -18, and -33 into their mature forms, IL-1β, IL-18, and IL-33.

Caspase-1 is key in activating pro-inflammatory cytokines.

Caspase-1 mediates the proteolytic processing of pro-IL-1β, pro-IL-18, and the propyroptotic factor gasdermin D (GSDMD).

Gasdermin D forms pores in the membrane of infected cells, facilitating the secretion of IL-1β/IL-18 and inducing the inflammation-associated cell death known as pyroptosis.

Caspase-1 induced inflammatory cytokines signal immune cells and recruit them to the site of damage playing a fundamental role in the innate immune system.

Caspase-4 and -5 bind to LPS, a molecule abundant in gram negative bacteria.

Caspases can induce an inflammatory response on a transcriptional level, promoting transcription of nuclear factor-κB (NF-κB), a transcription factor that assists in transcribing inflammatory cytokines such as IFNs, TNF, IL-6 and IL-8.

Caspases, are numbered in the order in which they were identified.