Cytolytic mechanisms: Self-destruction of mammalian cells by activation of endogenous hydrolytic enzymes

Cells contain a variety of hydrolytic enzymes that play important rules in regulation and turnover. Suitable subtrates for these enzymes are found within the cell itself, including essential structural and informational macromolecules, but a variety of mechanisms exist which prevent the cell's hydrolytic enzymes from prolonged attack on its own components. This situation makes it possible to envisage a class of cytolytic mechanisms in which hypothetical toxins could circumvent these controls allowing one or more of the cell's hydrolytic enzymes to attack its own essential structures, destroying them and leading to cell death. Of the hydrolytic enzymes found in cells, phospholipases, nucleases and proteases show the greatest promise for forming the basis of a cytotoxic mechanism of this type. Among these, phospholipases C and A₂ are the most promising, because there are numerous examples of exogenous phospholipase C and A₂ enzymes which function as effective toxins. The mechanisms by which these two enzymes lead to destruction of cell membranes are only partially understood, but it is reasonable to expect that prolonged activation of the corresponding endogenous enzyme would also lead to membrane destruction by a similar mechanism. Endogenous phospholipases C and A₂ have been identified in mammalian cells, where they are believed to play important roles in regulating the synthesis of prostaglandins and other arachidonic acid metabolites, and possibly to play a role in the regulation of other membrane-related phenomena by direct effects on membrane properties. In the case of phospholipase A₂ the products of its action on the major membrane-forming lipid in mammalian cells are two natural detergent lipids (lysolecithin and free fatty acids) which can alter membrane properties and the activities of membrane-associated enzymes. To date no toxin which activates an endogenous phospholipase C has been identified, but a series of toxins which activate endogenous phospholipase A₂ have been. Partial characterization of these enzymes has provided evidence for multiple, independently activatable phospholipases in a cloned mammalian cell line.