Low‐level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus

Abstract

For a long time, lysosomes were purely seen as organelles in charge of garbage disposal within the cell. They destroy any cargo delivered into their lumen with a plethora of highly potent hydrolytic enzymes, including various proteases. In case of damage to their limiting membranes, the lysosomes release their soluble content with detrimental outcomes for the cell. In recent years, however, this view of the lysosome changed towards acknowledging it as a platform for integration of manifold intracellular and extracellular signals. Even impaired lysosomal membrane integrity is no longer considered to be a one‐way street to cell death. Increasing evidence suggests that lysosomal enzymes, mainly cathepsin proteases, can be released in a spatially and temporarily restricted manner that is compatible with cellular survival. This way, cathepsins can act in the cytosol and the nucleus, where they affect important cellular processes such as cell division. Here, we review this evidence and discuss the routes and molecular mechanisms by which the cathepsins may reach their unusual destination.

Calpain-Independent Intracellular Protease Activity Is Elevated in Excitotoxic Cortical Neurons Prior to Delayed Calcium Deregulation and Mitochondrial Dysfunction

“…Activation of the Ca 2+ -dependent phospholipase PLA2G4A was recently reported to cause the translocation of a soluble lysosomal protease to the cytoplasm in rat cortical neurons and to promote lysosomal permeabilization in vivo following traumatic brain injury [ 33 ]. Lysosomes house numerous proteases, some of which exhibit altered activity at the neutral pH of the cytoplasm compared with the acidic pH of the lysosome [ 34 , 35 ]. Thus, it is possible that the modest cA-TAT fluorescence increase upon glutamate addition reflects activation of one or more proteases due to limited lysosomal permeabilization by Ca 2+ -dependent phospholipase, e.g., of a few lysosomes, whereas the larger increase upon DCD reflects more global lysosomal disruption.…”

Spatial localization of cathepsins: Implications in immune activation and resolution during infections

“…CTS, as stated before, may be released into the cytosol by controlled or uncontrolled lysosomal membrane permeabilization (LMP), leading to lysosomal dependent cell death (reviewed in ( 16 , 21 )). Extensive permeabilization leads to necrosis ( 72 ) while a less drastic release induces apoptosis ( 16 , 73 – 77 ).…”

“…CTS, as stated before, may be released into the cytosol by controlled or uncontrolled lysosomal membrane permeabilization (LMP), leading to lysosomal dependent cell death (reviewed in ( 16 , 21 )). Extensive permeabilization leads to necrosis ( 72 ) while a less drastic release induces apoptosis ( 16 , 73 – 77 ). Stringent controlled release of CTS will allow the cells to survive and physiologic responses to CTS either in the cytosol or in the nucleus ( 16 , 78 – 80 ).…”

“…Extensive permeabilization leads to necrosis ( 72 ) while a less drastic release induces apoptosis ( 16 , 73 – 77 ). Stringent controlled release of CTS will allow the cells to survive and physiologic responses to CTS either in the cytosol or in the nucleus ( 16 , 78 – 80 ). In the case of Salmonella infection a control of necrotic cell death was found associated with accumulation of active cathepsins in the nucleus ( 20 ).…”

“…Lysosomal enzymes were also found in less common locations, such as the cytosol and the nucleus ( 16 – 20 ). The cytosolic release of mature CTS is observed as a consequence of controlled lysosomal membrane permeabilization (LMP) or as a result of a more drastic damage ( 15 , 21 ).…”