Molecular Biologists Define a New Role for Oxysterol Binding Proteins

A recent paper discussed the role of a specialized type of lipid transfer protein and put forward the suggestion that these proteins have little to do with intracellular cholesterol transport but instead are critically involved in the processes of membrane assembly and lipid signaling.

Oxysterols are usually defined as oxygenated derivatives of cholesterol, though plant sterols can also be oxidized, and they are important as short-lived intermediates or end products in the catabolism or excretion of cholesterol. They are normally present in biological membranes and lipoproteins at trace levels only, though they can exert profound biological effects at these concentrations. However, they are always accompanied by a great excess of cholesterol.

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large gene family that differentially localize to the membranes of cellular organelles, reflecting a functional role in sterol signaling and/or transport. OSBP activity is divided between the endoplasmic reticulum (ER) and Golgi apparatus where it imparts sterol-dependent regulation of ceramide transport and sphingomyelin synthesis.

Investigators at Simon Fraser University (Burnaby, BC, Canada) worked with the ORPs encoded by the yeast OSH gene family (OSH1–OSH7) as a model system for intracellular lipid transport. These proteins are known to transfer oxysterols in the cell, but their role in cholesterol metabolism had not been defined.

In a paper published in the March 30, 2012, issue of the Journal of Biological Chemistry the investigators revisited the proposal that Osh proteins are sterol transfer proteins and presented new models consistent with known Osh protein functions. These models focused on the role of Osh proteins as sterol-dependent regulators of phosphoinositide and sphingolipid pathways. In contrast to their posited role as nonvesicular sterol-transfer proteins, they proposed that Osh proteins coordinated lipid signaling and membrane reorganization with the assembly of tethering complexes to promote molecular exchanges at membrane contact sites.

The investigators found that cholesterol binding interfered with ORPs' ability to bind to phosphatidylinositol 4-phosphate (PI4P), which is a precursor of phosphatidylinositol (4, 5)-bisphosphate. PI4P is prevalent in the membrane of the Golgi apparatus and is important for cell growth.

“The assumption was that ORPs bind and transport cholesterol inside cells in a similar fashion to how lipoproteins bind and move around the fat outside cells through the blood stream,” said first author Dr. Chris Beh, associate professor of molecular biology and biochemistry at Simon Frazer University. "Our findings told us that ORPs probably have nothing to do with moving around cholesterol within cells. Rather cholesterol binding puts the brakes on ORP's ability to bind to PI4P, which, if left unchecked, could accelerate cell growth like crazy. Given that uncontrolled cell growth is a key feature of cancer, this means gaining a better understanding of the true purpose of cholesterol-binding within cells could be important in cancer treatment.”

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