Mon. May 23rd, 2022

Confocal microscopy image showing SNX13 protein (green) in areas of the endoplasmic reticulum that come in contact with lipid droplets (blue) and lysosomes in which the BMP lipid is present (red).

Confocal microscopy image showing SNX13 protein (green) in areas of the endoplasmic reticulum that come in contact with lipid droplets (blue) and lysosomes in which the BMP lipid is present (red).

From left to right the lecturers from the Faculty of Medicine and Health Sciences Carles Enrich and Albert Lu, the first author of the article.

From left to right the lecturers from the Faculty of Medicine and Health Sciences Carles Enrich and Albert Lu, the first author of the article.

A team from UB and August Pi of the Sunyer Biomedical Research Institute (IDIBAPS) identified a mechanism involved in the movement of cholesterol inside the cells. The study, published in the Journal of Cell Biology, shows how the SNX13 protein plays a key role when this lipid is transported outside the liposomes, organelles that perform cellular digestion. These results may have implications for the future development of treatments for pathologies caused by dysfunctions of intracellular cholesterol transport, such as Niemann-Pick type C1 disease.

The study includes the participation of lecturers from the Faculty of Medicine and Health Sciences at UB and CELLEX Biomedical Research Center (IDIBAPS-UB) Albert Lu, first author of the article, and Carles Enrich together with researchers from Stanford University.

The harmful effects of unbalanced cholesterol levels

Most of the cholesterol that the cells use comes from outside and reaches the lysosomes, where it is distributed to different intracellular spaces. However, there are still unresolved issues related to the precise molecular events that regulate the release of cholesterol from this organelle and its transport toward the membrane and endoplasmic reticulum of the cell. The purpose of this study has been to study the mechanism, thanks to which cholesterol exists, the lysosomes. “This process requires the coordinated action of NPC1 and NPC2 transporters, which together with bis (monoaclyglycero) phosphate (BMP) lysosomal lipid mobilize and export the free cholesterol,” notes Carles Enrich.

The regulation of the intracellular trade in cholesterol and the amount that the cellular organelles receive is important for the balance – or homeostasis – of cholesterol in the cell. Faults or dysfunctions in its transport cause an imbalance that causes disorders such as Niemann-Pick type C disease. This pathology, which has no current cure, is produced by mutations in the lysosomal cholesterol transporters NPC1 and NPC2. This disease prevents cholesterol and other fats from being metabolized normally and has serious effects on the liver, spleen and brain.

Genome-wide genetic screening of the CRISPR / Cas9 type

To identify the regulators of cholesterol balance, researchers performed CRISPR / Cas9-type genetic screenings in the genome. This method allows a massive and parallel study of the human genome regarding a specific biological process, which generates a large amount of data. In this study, the screening was used under normal conditions, but also blocking of the NPC1 protein to identify cellular elements that can export cholesterol in parallel with this transporter.

This strategy enabled the identification of genes that, when removed, alter intracellular cholesterol or BMP levels. “Our genetic screenings identified a large number of genes involved in the metabolic regulation of cholesterol and BMP, the role of which was hitherto unknown. In addition, we confirmed a close correlation and regulation between the levels of these lipids,” notes Albert Lu.

One of the molecules involved in this process is that SNX13, a protein in the endoplasmic reticulum that negatively regulates the exit of cholesterol from lysosomes to the plasma membrane, thus reducing the amount of this lypid. “Given the lack of function of NPC1, the reduction of SNX13 caused a redistribution of lysosomal cholesterol toward the plasma membrane, indicating that SNX13 could be an important regulator in this cholesterol transport pathway,” says Albert Lu.

An unexpected view of regulatory mechanisms

These results provide an unexpected view of the regulation of these lipids, as there are a few alternative mechanisms – and most of them are unknown – that allow cholesterol to leave when the NPC1 transporter is inhibited or attenuated. “We described an alternative pathway regulated by anexin-A6, and with this new study, we provide new evidence showing that there may be alternative pathways for lysosomal cholesterol in parallel with NPC1,” highlights Carles Enrich.

The finding of molecules capable of reversing the effects caused by NPC1 dysfunction, such as SNX13, could involve the existence of “future therapeutic targets in the treatment of Niemann-Pick type C disease, as a better knowledge of the molecules , participating in the contact between organelles can allow manipulation of the transport of lipids and ions and re-establish cellular homeostasis, ”the researchers conclude.

Reference Article:

Lu, A .; Hsieh, F .; Sharma, BR; Vaughn, SR; Berig, C .; in Pfeffer SR «CRISPR screenings for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export». Journal of Cell Biology, December 2021. Doi: https://doi.org/10.1083/jcb.202105060

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