A research team 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 transporting this lipid outside the liposomes, organelles that conduct cellular digestion. These results could have implications in the future developing treatments against pathologies caused by dysfunctions in the intracellular cholesterol transport, such as the Niemann-Pick type C1 disease.
Most part of the cholesterol that cells use comes from the outside, reaching the lysosomes where it is distributed to different intracell compartments. However, there are still unsolved questions related to the precise molecular events that regulate the exit of cholesterol from this organelle and its transport towards the membrane and the cell endoplasmic reticulum.
The objective of this study has been to study the mechanism thanks to which cholesterol exists the lysosomes. “This process requires the coordinate action of NPC1 and NPC2 transporters that, together with the bis(monoaclyglycero)phosphate (BMP) lysosomal lipid, mobilize and export the free cholesterol”, notes the author.
The regulation of the intracellular trafficking of cholesterol and the quantity the cellular organelles receive is important for the balance —or homeostasis— of cholesterol in the cell. Errors 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 metabolised normally and has serious effects on the liver, spleen and the brain.
In order to identify the regulators of cholesterol balance, researchers conducted CRISPR/Cas9-type genetic screenings in the genome. This methodology allows an interrogation in a massive and parallel manner, of the human genome regarding a specific biological process, generating a great amount of data. In this study, the screening was applied under normal conditions, but also blocking the NPC1 protein in order to identify cell elements that can export cholesterol parallelly to this transporter.
This strategy enabled the identification of genes that, when removed, alter the intracellular cholesterol or BMP levels. “Our genetic screenings identified a high number of genes involved in the cholesterol and BMP metabolic regulation, whose role was unknown to date. In addition, we confirmed a tight correlation and regulation between the levels of these lipids”, notes another author.
One of the involved molecules in this process is that SNX13, a protein in the endoplasmic reticulum that negatively regulates the exit of cholesterol from lysosomes to the plasmatic membrane, thus reducing the amount of this lypid. “Given the lack of the function of NPC1, the reduction of SNX13 caused a redistribution of lysosomal cholesterol towards the plasmatic membrane, which indicates that SNX13 could be an important regulator in this cholesterol transport pathway”, says the author.
These results provide with an unexpected view of the regulation of these lipids, since there are a few alternative mechanisms —and most of them are unknown— that allow cholesterol to exit when the NPC1 transporter is inhibited or muted. “We described an alternative pathway regulated by anexin-A6, and with this new study we provide new evidence showing that there can be alternative exit routes for the lysosomal cholesterol parallelly to the NPC1”, highlights the author.
The finding of molecules able to reverse the effects caused by the NPC1 dysfunction, such as SNX13, could involve the existence of “future therapeutic targets in the treatment of Niemann-Pick type C disease, since a better knowledge of the molecules that take part in the contact between organelles can allow the manipulation of the transport of lipids and ions and re-establish the cellular homeostasis”, conclude the researchers.
https://rupress.org/jcb/article-abstract/221/2/e202105060/212937/CRISPR-screens-for-lipid-regulators-reveal-a-role
Latest News
Metabolic rewiring promotes…
By newseditor
Posted 18 Apr
A drug to prevent flu-induc…
By newseditor
Posted 18 Apr
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Other Top Stories
How brain uses bodily signals to regulate fear
Read more
Separating fact from fiction for "anti-aging" diets
Read more
The link between vitamin D and inflammation
Read more
Chronic stress and depression related protein crystallized!
Read more
Thousands of novel brain-expressed gene isoforms identified!
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
How does the microbiota con…
By newseditor
Posted 18 Apr
The integrated stress respo…
By newseditor
Posted 18 Apr
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar