Endolysosomal proteolysis and its regulation

Abstract

The endolysosomal system comprises a unique environment for proteolysis, which is regulated in a manner that apparently does not involve protease inhibitors. The system comprises a series of membrane-bound intracellular compartments, within which endocytosed material and redundant cellular components are hydrolysed. Endocytosed material tends to flow vectorially through the system, proceeding through the early endosome, the endosome carrier vesicle, the late endosome and the lysosome. Phagocytosis and autophagy provide alternative entry points into the system. Late endosomes, lysosome/late endosome hybrid organelles, phagosomes and autophagosomes are the principal sites for proteolysis. In each case, hydrolytic competence is due to components of the endolysosomal system, i.e. proteases, lysosome-associated membrane proteins, H+-ATPases and possibly cysteine transporters. The view is emerging that lysosomes are organelles for the storage of hydrolases, perhaps in an inactivated form. Once a substrate has entered a proteolytically competent environment, the rate-limiting proteolytic steps are probably effected by cysteine endoproteinases. As these are affected by pH and possibly redox potential, they may be regulated by the organelle luminal environment. Regulation is probably also affected, among other factors, by organelle fusion reactions, whereby the meeting of enzyme and substrate may be controlled. Such systems would permit simultaneous regulation of a number of unrelated hydrolases.

Harboring of Particulate Allergens within Secretory Compartments by Mast Cells following IgE/FcεRI-Lipid Raft-Mediated Phagocytosis

“…Indeed, the fusion of the secretory compartments with nascent allergen-containing phagosomes in MCs observed in these studies is analogous to the fusion of conventional lysosomes with late endosomes. However, unlike the destructive fate of cargo processed via the classical endosome-lysosome pathway (33), our data suggest that allergens harbored within the secretory compartments of MCs fail to be degraded. This may indicate that the secretory compartments of MCs are inherently defective in their degradative potential, which is consistent with their role as organelles for the storage of inflammatory mediators.…”

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

“…For example, because their in vitro study used total lysosomal extracts instead of purified individual lysosomal cathepsins for the Bid cleavage assays, it seems possible that other unidentified lysosomal components besides cathepsins could have been responsible for the cleavage and activation of Bid. Namely, there are more than 50 hydrolytic enzymes present in lysosomes, 37 and some are already implicated in apoptosis. 38,39 To help resolve whether cathepsins are in fact the lysosomal components that cause Bid cleavage in vitro, additional follow-up studies aimed at identifying which cathepsins can cleave Bid are currently underway.…”

Chymotrypsin B Cached in Rat Liver Lysosomes and Involved in Apoptotic Regulation through a Mitochondrial Pathway

“…These unique conditions impose stringent requirements that can be met almost exclusively by cathepsins in their mature forms. In contrast, Ctrb is incompatible with the denaturing luminal environment, with acidification leading to substantial loss of its activity (20). We would like to suppose that lysosomal Ctrb must take on a strategy to protect from the deleterious conditions in the lysosomal lumina and sustain its potential as a neutral serine protease.…”