The proper intracellular distribution of sterols such as cholesterol is critical for numerous cellular functions, including signal transduction and protein trafficking. Sterols are moved among cellular compartments by both vesicular and poorly understood nonvesicular pathways. We have previously shown that a non-vesicular pathway moves sterols from the plasma membrane (PM) to the endoplasmic reticulum in the yeast S. cerevisiae. We found that this transport requires oxysterol-binding protein (OSBP)-related proteins (ORPs), a large family of lipid-binding proteins that is conserved from yeast to humans. In addition, we have been able to show that some of these yeast ORPs transport sterols and other lipids in vitro. Thus, lipid transport is one of the functions of this important class of proteins. We also found that sterol transport by OSBPs is regulated by particular phosphoinositides (PIPs). Because different PIP-species are enriched in various cellular compartments, PIP-stimulation of ORPs likely serves to regulate the movement of sterols (and possibility other lipids) to particular organelles by ORPs, perhaps in response to cell signaling events. This work is described in a paper in the Journal of Cell Biology. We have continued characteriztion of the yeast ORPs. We have found that all have more than one membrane binding surface and we are in the process of determining how these proteins bind membranes and extract lipids. This work will be described in a manuscript that has been submitted. In a second project, we have established a system to study phospholipids transport between the ER and mitochondria. We find that a conserved complex of ER proteins is required for phospholipid exchange between these organelles. This work is described in a manuscript that will be submitted for publication soon.
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