The Endolysosomal System in Cell Death and Survival

The endocytic pathway is a system specialized for the uptake of compounds from the cell microenvironment for their degradation. It contains an arsenal of hydrolases, including proteases, which are normally enclosed in membrane-bound organelles, but if released to the cytosol can initiate apoptosis signaling pathways. Endogenous and exogenous compounds have been identified that can mediate destabilization of lysosomal membranes, and it was shown that lysosomal proteases are not only able to initiate apoptotic signaling but can also amplify the apoptotic pathways initiated in other cellular compartments. The endocytic pathway also receives cargo destined for degradation via the autophagic pathway. By recycling energy and biosynthetic substrates, and by degrading damaged organelles and molecules, the endocytic system assists the autophagic system in resisting apoptotic stimuli. Steps leading to lysosomal membrane permeabilization and subsequent triggering of cell death as well as the therapeutic potential of intervention in lysosomal membrane permeabilization will be discussed.Since the discovery of lysosomes in 1950s (de Duve et al. 1955), the concept of the endocytic pathway has changed. Although there has been huge progress in understanding the molecular mechanisms of targeting and fusion of organelles, several conceptual dilemmas have not been completely resolved. The primary function of the endocytic pathway is bulk degradation and recycling of the internalized material and redundant cellular components. Over the years, additional functions have been associated with it. Endosomes and lysosomes can fuse with the plasma membrane to repair it and to release the accumulated nondegradable material (Medina et al. 2011). Intraluminal vesicles are the source of exosomes, which have multiple functions, especially for the immune system (Ludwig and Giebel 2012). Endosomes have numerous functions in fighting infections: they can signal the presence of pathogens through Toll-like receptors, they are the site of antigenic peptide generation and their assembly with major histocompatibility complex class II molecules, and they can also kill residing pathogens (Gruenberg and van der Goot 2006). Because of a high content of proteases, de Duve (1959) coined the figurative term “suicide bags” for lysosomes, a concept since supported by a wealth of experimental reports (de Duve 1959). Perhaps the best examples of this concept are natural killer cells and cytotoxic T cells. Both have specialized lysosome-related organelles, secretory granules, that contain perforin and granzyme B, which can mediate apoptosis in the target cell (Blott and Griffiths 2002; Trapani and Smyth 2002). However, every cell can potentially become a victim of its own lysosomal hydrolases, especially if lysosomal membranes are destabilized so that the enzymes can escape into the cytosol. These offer great potential to exploit scenarios for therapy for certain diseases, most importantly cancer. On the other hand, by enabling degradation of the material sequestered by autophagy, the endocytic pathway can assist autophagy in counteracting apoptosis when cells are challenged with an apoptotic stimulus (Repnik and Turk 2010; Hafner Česen et al. 2012; Repnik et al. 2012).