Abstract
Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane trafficking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions. A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we first discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We then discuss whether lysosomal exocytosis can be manipulated to correct lysosomal and cellular dysfunction caused by excessive lipid storage, providing a potentially general therapeutic approach for LSDs.
Highlights
Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks
Endocytosis or phagocytosis of extracellular particles or plasma membrane proteins begins with the invagination of the plasma membrane to form endocytic vesicles, which undergo a series of maturation processes to first become early endosomes, and late endosomes [excellently reviewed in (5)] (Fig. 1)
Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of various biomaterials and macromolecules, such as membranes, proteins, polysaccharides, and complex lipids into their
Summary
Lipids, such as sphingolipids, glycolipids, phospholipids, and cholesterol, are the essential structural constituents of the plasma membrane and the membranes of intracellular compartments (1, 4). Defective membrane trafficking and catabolite export could cause a “traffic jam”, resulting in secondary lipid storage in the lysosome (Fig. 2) (17). Primary accumulation of undigested insoluble lipids may cause a traffic jam, slowing down membrane trafficking and sorting, affecting the delivery of lysosomal hydrolases (3, 17). Progressive accumulation of undigested lipids and protein aggregates, primarily or secondarily, leads to build-up of enlarged (>500 nm) but dysfunctional lysosomes These enlarged “lysosomes” are presumably endolysosomes and autolysosomes, which under normal conditions are used to regenerate new lysosomes via the process of lysosome reformation, upon completion of lysosomal degradation (15). A new therapeutic strategy for lysosomal storage disorders 997 lysosomal substrates, most LSD cells exhibit an increase in the basal autophagy and in the expression levels of housekeeping lysosomal proteins such as Lamp-1 (8, 22). In this review we will first describe the core machinery of lysosomal exocytosis, and discuss how it can be regulated for the purpose of cellular clearance as a therapeutic target for LSDs
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