Abstract
In specialized cell types, lysosome-related organelles support regulated secretory pathways, whereas in nonspecialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol-storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in nonspecialized cells and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel mucolipin-1, as well as FYCO1, the AP1 adaptor, and its partner Gadkin. We conclude that endo-lysosomes in nonspecialized cells can acquire secretory functions elicited by cyclodextrin and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.
Highlights
In specialized cell types, lysosome-related organelles support regulated secretory pathways, whereas in nonspecialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium
In the Niemann-Pick type C (NPC) lysosomal storage disease, mutation of NPC1 or NPC2 causes the accumulation of LDL-derived cholesterol in late endocytic compartments, but the functions of the NPC1 and NPC2 proteins remain incompletely understood [68]
The accumulation of storage materials in NPC endosomes eventually leads to a traffic jam and a collapse of endosomal membrane dynamics [69, 70], accompanied by defects both in cholesterol movement to the ER and transcriptional regulation of cholesterol metabolism [2,3,4]
Summary
Lysosome-related organelles support regulated secretory pathways, whereas in nonspecialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. We report that cyclodextrin triggers the secretion of the endo/lysosomal content in nonspecialized cells and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We conclude that endo-lysosomes in nonspecialized cells can acquire secretory functions elicited by cyclodextrin and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.—Vacca, F., S. Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells. The precise mechanism of export remains unclear It is not clear how cholesterol is transferred from late endosome/ lysosomes to reach the regulatory pool in the ER. Several direct routes have been proposed [13], but recent findings indicate that the plasma membrane may be the primary destination of LDL-derived cholesterol before reaching the ER [14]. This view is consistent with the earlier notion that cholesterol rapidly equilibrates between the plasma membrane and the regulatory ER pool [15]
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