Caspases

By Jennifer McDowall

Cells are programmed to survive, die or proliferate through a complex system of regulatory controls that are key to the organisation of multicellular organisms. In particular, programmed cell death, or apoptosis, is required to control many aspects of normal physiology in animals, including embryonic development, homeostasis, aging and immunity. During embryonic development, apoptosis is involved in the formation of biological patterns, as well as in generating the diversity of cells that make up different tissues. For example, in the developing mouse embryo, apoptosis helps create the correct tooth pattern by eliminating vestigial tooth primordial, a well as shaping the germs in functional teeth. The maintenance of tissue homeostasis is also aided by apoptosis, which acts to remove damaged, aged, autoimmune or malignant cells. The elimination of these apoptotic cells by phagocytes is important to prevent the release of intracellular contents, including digestive enzymes, into the surrounding tissue where they could cause damage. The onset of autoimmune disorders is thought to be linked to the inefficient removal of apoptotic cells. In addition, apoptosis plays a role in the defence against pathogenic viruses and microbes by targeting infected cells for destruction and removal, as well as activating inflammatory responses. In some cases, the microbes can fight back, for instance with Cowpox virus, which produces a serine protease that inhibits the cellular response to infection. Aberrant regulation of apoptosis at any time from embryogenesis to adulthood can result in inappropriate cell loss or pathological cell accumulation, culminating in a variety of diseases from neurogenerative disorders (excessive apoptosis) to cancer (insufficient apoptosis). For example, naturally apoptosis-resistant precursor cells are the origin of retinoblastoma.

Apoptosis is a complex processes involving a cascade mechanism that employs many proteins. However, the key enzymes in this process are the caspases, a family of cysteine proteases that control and mediate the apoptotic response.

Caspases, Key Apoptotic Proteins

Virtually all animal cells contain caspases, but they occur as inactive zymogens that can do no harm. There are various triggers that can lead to their activation, which usually occurs through proteolytic processing of the zymogen at conserved aspartic acid residues. Needless to say, their activation and suicidal function is highly regulated. Once activated caspases act as cysteine proteases, using a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The name “caspase” denotes their function: Cysteine-dependent ASPartyl-specific proteASE. There are many such caspases within an organism, which work together in a proteolytic cascade to activate themselves and one other. Cascades are effective means of amplifying a signal to give a much larger response than could be achieved through a single enzymatic reaction. The high degree of specificity of caspases enables a precisely controlled cascade process, rather than indiscriminate proteolysis. Caspases have several roles within the cascade: as triggers of the cell death process, as regulatory elements within it, and as effectors of cell death itself, the latter usually being activated by caspases acting earlier in the cascade. At the end of this cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases to target a cell for destruction by disintegrating its contents, including its DNA.

Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells.

Next: What Makes a Cell Commit Suicide?