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Alternative route for cholesterol

STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites.

Wilhelm LP(1)(2)(3)(4), Wendling C(1)(2)(3)(4), Vedie B(5), Kobayashi T(4)(6), Chenard MP(1)(4)(7), Tomasetto C(8)(2)(3)(4), Drin G(9), Alpy F(8)(2)(3)(4).

EMBO J May 15, 2017


April 4, 2017

Cholesterol is a molecule of vital importance. In a new study, the team of Catherine-Laure Tomasetto at the IGBMC reveals the involvement of the STARD3 protein in the distribution of cellular cholesterol. This protein forms membrane contacts between two cell organelles, promoting cholesterol transport from one organelle to the other along a new route. This work is published on April 4th 2017 in the EMBO Journal.

Origins of cellular cholesterol
Cholesterol is a component of biological membranes essential to life. A cell has two ways to obtain cholesterol: either it captures blood lipoproteins and internalizes them through the endocytic pathway, or it produces cholesterol in the endoplasmic reticulum, a network covering the inside of the cell, which synthesizes most lipids. Once captured or synthesized, cholesterol is redistributed in all cell membranes through mechanisms which remain, for some of them, to be clarified.

 

Cholesterol transport pathways
Since cholesterol is insoluble in water, its movements are very limited within the cell. To ensure its transport, the cells have specialized transporters. The team of Catherine-Laure Tomasetto is interested in one of them, the STARD3 protein, whose role was until then little known. In a new collaborative study with the team of Guillaume Drin at the IPMC (Nice), the researchers unraveled some of its mystery. STARD3 is a protein tied to late endosomes, cellular organelles that ensure communication between the outside and the inside of the cells. In the cell, STARD3 sticks to the VAP protein, a protein itself bound to the endoplasmic reticulum. This association attaches endosomes to the endoplasmic reticulum creating membrane contact sites. At these sites, the membranes of the two organelles are very close (<30nm), facilitating communication and exchange. In this study, the researchers demonstrated that these membrane contact sites between endosomes and the endoplasmic reticulum form a bridge, allowing STARD3 to transfer cholesterol from the endoplasmic reticulum membrane to that of the endosome, thereby rerouting some of the cholesterol intended for the plasma membrane.

These results identify a new pathway regulating the flow of cholesterol in the cell. They provide news clues on how cells balance the two cholesterol sources, and may help to better understand the mechanisms of some neurodegenerative or cardiovascular diseases characterized by alterations in cholesterol distribution.

 

This study was funded by the INCA, the Fondation pour la Recherche Médicale (FRM), the Ligue contre le cancer, the Ara Parseghian Medical Research Foundation and the association Vaincre les maladies lysosomales.

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