Interrelationship between the Non-Vesicular Transport of Sterols and Their Distribution between the Rafts and the...

Sterols significantly affect the barrier properties of the membrane, which might explains the fact that their concentration is maximal in the plasma membrane (PM). Together with sphingolipids, sterols form rafts, i.e., bilayer regions whose physicochemical properties differ from those of the surrounding PM. The presence of rafts allows membrane proteins to choose the lipid environment optimal for their functioning (in terms of thickness, rigidity, spontaneous curvature, and lateral pressure profile of the bilayer). The ratio between sterols and sphingolipids in the rafts is close to stoichiometric. Theoretically, excess sterol outside the rafts can critically reduce the degree of order of membrane phospholipids. Sterols are synthesized in the endoplasmic reticulum (ER). The active (against the concentration gradient) transport of sterols from the ER to the PM is driven by proteins of the Osh family, while Lam proteins provide passive reverse transport of sterols from the PM to the ER. Inactivation of Osh proteins does not reduce the total level of sterols in the PM but reduces the rate of their movement inside the PM (the mechanisms underlying this effect remains unclear). Therefore, the vesicular transport of sterols from the ER to the PM is probably more active than the non-vesicular transport carried out by Osh proteins. Since sterols are more rigidly anchored and less sterically accessible in the rafts than outside them, we suggested that Lam proteins transport excess sterols from the non-raft phase of the PM to the ER, and Osh proteins return them back to the PM. In this way, the mutual activity of the Osh and lam proteins provides the rotation of sterols between the non-raft fraction of the PM and rafts, with the enrichment of the latter. It is possible that with a decrease in the sterol concentration in the non-raft fraction of the membrane, the rate of the Lam-dependent transport decreases since the degree of order of phospholipids and, consequently, the strength of retention of sterol molecules in the membrane increases, which might represent a mechanisms maintaining the concentration and distribution of sterols in the PM.