Request for Funding

Mentor: Mike Brown, MD
Department: Molecular Genetics
Room number: L5-238
Mail Code: 9046
Phone number: 8-2179
E-mail: mike.brown@utsouthwestern.edu
Project title: Identification of oxysterol receptor that regulates SREBP processing

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable):

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:

SREBPs are transcription factors that activate the genes needed for cholesterol synthesis and LDL uptake. SREBPs are synthesized as inactive precursors bound to the ER membrane and must be proteolytically cleaved by Golgi-localized proteases in order to become activated. The proteolytic cleavage of SREBP is regulated by cellular cholesterol levels and by two ER membrane proteins called SCAP and Insig. Under conditions where cells need to synthesize cholesterol or take up LDL, SCAP escorts SREBP to the Golgi for proteolytic activation. When cells are treated with cholesterol or with 25-hydroxycholsterol (25-HC), SCAP binds tightly to Insig and is thus prevented from escorting SREBP to the Golgi.

Recent work suggests that cholesterol and 25-HC use different mechanisms to promote the SCAP-Insig interaction and inhibit SREBP activation. Whereas cholesterol exerts its effect by directly binding to SCAP and altering SCAP conformation, 25-HC does not bind directly to SCAP and does not alter SCAP conformation. These results suggest that 25-HC binds to a receptor distinct from SCAP. In order to identify this receptor, I will use a photoactive derivative of 25-HC which suppresses SREBP processing at very low concentrations, but does not bind to SCAP or change SCAP's conformation. The photoactive 25-HC will be used to identify proteins that specifically crosslink to it. We will then test the role of these 25-HC receptors in regulation of SREBP processing.

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