Two recent papers1, 2 have expanded the role of the proteolytic mediators of apoptotic cell death beyond caspases. The newly discovered proteases capable of triggering pro-apoptotic changes in mitochondria are in fact old-fashioned proteins confined to the lysosomes and known for their involvement in non-specific cellular waste disposal, ie the cathepsins.

Knife and fork are evolutionary optimized tools to dine in a neat and efficient way'. Using this analogy of dining for cell demise and cutlery for caspases, two evident questions arise: are knife and fork sufficient tools in all cases±and, are they always necessary? The first question brings to mind an array of other sophisticated tools developed for eating specific foods like eg lobster or fondue. In the cell death world such additional gadgets could correspond to other proteases like the above mentioned cathepsins. 3 Formerly, cathepsins were thought to lead to cellular autolysis and damage of neighboring cells during necrosis (Figure 1). Accordingly, lysosomes were regarded assuicide bags' that would release unspecific digestive enzymes after rupturing during uncontrolled cellular stress. Recent in vitro4±6 as well as in vivo7 data suggest, however, that cathepsins may also act as mediators of programmed cell death. The fact that the frequently used caspase inhibitor zVAD-fmk efficiently blocks cysteine cathepsins like cathepsin-B (cathB), 8 further emphasizes the need for a re-evaluation of the existing literature on the relative roles of caspases and cathepsins in a number of apoptosis paradigms. How is it possible that a specific cell death program can be triggered by the rather unspecific digestive power of lysosomal proteases? It appears as if a specific translocation process could be a key to the understanding of this phenomenon. For instance the selective translocation of cathB from lysosomes to cytosol and nucleus is well documented for bile salt-induced hepatic apoptosis. 5 Similarly, there is clear evidence of early cathepsin-D translocation from secondary lysosomes to the cytosol under conditions of oxidative stress induced apoptosis. 9, 10 A second possibility is a quantitative relationship between the amount of lysosomal rupture and the mode of cell death. According to this model, low stress intensities trigger a limited release of lysosomal enzymes to the cytoplasm followed by apoptotic death, while high intensity stresses would lead to generalized lysosomal rupture and rapid cellular necrosis. 11 A causal association between a limited