Cathepsins: Getting in shape for lysosomal proteolysis

Besides their pivotal functions in general cellular protein turnover, cathepsins play important roles in a diverse range of other physiological processes which include tissue remodelling during embryogenesis and development, programmed cell death, autophagy, prohormone and neuropeptide processing, antigen presentation, wound healing and bone resorption. Furthermore, substantial experimental evidence has been accumulated that cathepsins are of pathological relevance in disease states such as cancer, arthritis, osteopetrosis, pancreatitis, cholestatic liver disease, and epilepsy (Mohamed and Sloane 2006; Vasiljeva et al. 2007; Turk and Turk 2009; Reiser et al. 2010). To prevent tissue damage due to unwanted proteolysis, the activities of cathepsins have to be strictly controlled in situ. The main regulatory pathways rely on restricting the subcellular localization of these proteases to lysosomes, the presence of specific cathepsin inhibitors in other cellular compartments, and their initial synthesis as latent proenzymes (Cygler and Mort 1997; Mort and Buttle 1997; Turk et al. 2001b). Interference with any of these control mechanisms can lead to pathological consequences. It is therefore crucial to understand the molecular basis of cathepsin biosynthesis and intracellular transport as well as the mechanisms leading to activation of their precursors in a cellular context.