Research

Regulation of Sterol Homeostasis

Elevated serum cholesterol is a primary risk factor for heart disease. Cells release excess cholesterol into the blood because a high level of intracellular cholesterol is toxic. A negative feedback mechanism prevents cholesterol overaccumulation by regulating SREBP, a membrane-bound transcription factor that activates genes required for cholesterol biosynthesis and uptake of cholesterol-rich lipoproteins. Sterols negatively regulate the activity of SREBPs by blocking the ER to Golgi transport of SREBPs and their subsequent proteolytic activation. When cells are depleted of cholesterol, SCAP escorts SREBP from the ER to the Golgi. Sterols inhibit transport of SREBP by blocking entry of SREBP-SCAP into ER transport vesicles. This ER retention is mediated by the membrane protein Insig that binds SCAP-SREBP in the presence of high sterols.

To better understand this vesicle sorting event and to identify novel regulators of SREBP, we are studying orthologs of SREBP, SCAP and Insig in the fission yeast Schizosaccharomyces pombe, called Sre1, Scp1, and Ins1, respectively. New discoveries will be confirmed using mammalian tissue culture.

Current projects in the lab include:

1. Performing genetic selections and screens to identify positive and negative regulators of Sre1 activity
2. Characterization of the sterol signal that controls Sre1 proteolysis
3. Understanding the function of yeast Insig, Ins1, in sterol homeostasis