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.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

“…19 CTSL and other lysosomal proteases are released into the cytosol upon apoptosis induction. 23 The fact that FH does not become degraded within the apoptotic cells implies that it remains functional after internalization. Indeed, we found that FH acts as cofactor for CTSL-mediated cleavage of C3 into C3b, which may be due to direct binding of FH to CTSL.…”

Caspases rule the intracellular trafficking cartel

“…In the absence of functional retromer, autophagy and lysosomal degradative capacity are perturbed leading to abnormal accumulation of material in lysosomes and lysosomal storage diseases [105]. The lysosomes are also of vital importance to the cell as they can trigger apoptotic cell death when their integrity or functions are compromised [106][107][108].…”

Anα-Acetoxy-Tirucallic Acid Isomer Inhibits Akt/mTOR Signaling and Induces Oxidative Stress in Prostate Cancer Cells

“…Highly reactive ROS produced in lysosomes as a result of Fenton-type reactions can damage the lysosomal membrane and induce release of lysosomal cargo into the cytosol, thereby promoting apoptosis (Repnik et al, 2013). Overall, this leads to a point of no return during the commitment stage of apoptosis and suggests that apoptosis induced by tirucallic acids proceeds mainly through the mitochondrial pathway.…”

“…Rapamycin, which promotes autophagy, even protects cells against a range of proapoptotic insults. It is believed that autophagy, which enhances clearance of mitochondria, reduces cytosolic cytochrome c release and downstream caspase activation thereby promoting survival (Repnik et al, 2013). All forms of autophagy, in turn, rely on lysosomes for the subsequent degradation of their cargo.…”

“…Under conditions of oxidative stress, excess ROS diffusing into lysosomes and autolysosomes fully loaded with autophagic cargo can easily destabilize membranes and cause lysosomal membrane permeabilization (Aits and Jaattela, 2013). Furthermore, lysosomal membrane dysfunction not only leads to the release of lysosomal proteases into the cytosol but also reduces the degradation rate of the endocytotic system, impairing the cytoprotective role of autophagy and lowering the apoptotic threshold (Repnik et al, 2013). Indeed, in cells treated with aATA(8,24) the increased ROS and superoxide production might be amplified by the positive feedback loop between mitochondria and acidic vesicular organelles, whereas in cells treated with rapamycin, the ROS production and the feedback loop are absent.…”