The endolysosomal system in cell death and survival

Abstract

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.

Figure 1.

Endocytic pathway. (A) A schematic representation of the endocytic pathway (details are explained in the text). EE, early endosome; ILV, intraluminal vesicle; MVB, multivesicular body; ECV, endosome carrier vesicle; LE, late endosome; TGN, trans-Golgi network. (B) A transmission electron micrograph showing endocytic organelles in RAW cells, labeled with three different sizes of gold particles. Cells were pulsed with a 15-nm gold–bovine serum albumin (BSA) conjugate (block arrows) for 4 h and chased for 24 h to label LEs. During the last 6 min of culture, cells were fed with a 5-nm gold–BSA conjugate (thin arrows) to label endocytic vesicles and EEs. A thin Tokuyasu section was labeled with anti-LAMP2 antibody in a three-step reaction involving the primary antibody, a secondary rabbit anti-mouse antibody, and a 10-nm gold–protein A conjugate (thick arrows). Scale bar, 500 nm.

Figure 2.

The role of lysosomes in apoptosis. Lysosomotropic detergents, reactive oxygen species (ROS), acid sphingomyelinase (A-SMase), Fenton reaction, etc., can trigger lysosomal membrane permeabilization (LMP), during which lysosomal contents are released into the cytosol. Cathepsins can process BID and degrade antiapoptotic BCL-2 proteins, which together enable the oligomerization of BAX and BAK proteins into mitochondrion membrane-spanning pores, causing mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. Cathepsins can degrade inhibitors of caspases, such as XIAP, further promoting caspase activation downstream of MOMP, along with XIAP antagonists SMAC/DIABLO and HtrA2/Omi. The extrinsic apoptotic pathway is represented with gray lines and text.