Lysosomal proteases in cell death

Abstract

Apoptosis is a highly organized, energy-dependent program by which multicellular organisms eliminate damaged, superfluous, and potentially harmful cells. While caspases are the most prominent group of proteases involved in the apoptotic process, the role of lysosomes and, more particularly, of lysosomal cathepsins in cell death has only been recently unmasked. The release of cathepsins from the lysosomal lumen to the cytosol is a precondition for their participation in the regulation of apoptosis and has been described in response to a variety of death stimuli such as members of the cell-surface TNF receptor family, chemotherapeutic drugs, and nonreceptor-mediated apoptotic agents. This lysosomal membrane permeabilization often relies on the activation of the intrinsic apoptosis pathway, which involves mitochondrial membrane permeabilization and the consequent release of the proapoptotic mitochondrial proteins into the cytosol. These factors lead to caspase activation and, finally, cell death. The aim of this chapter, emphasizing the role of lysosomal proteases in apoptosis, is to summarize past and recent findings that provide an insight into the mechanisms by which these hydrolases modulate apoptosis and also those that strongly argue for their role in the control of pathogenic cell dismantling.