Regulation of Lipid Homeostasis
Maintenance of lipid homeostasis is essential for cell survival, and disruptions to lipid homeostasis lead to heart disease and non-alcoholic fatty liver disease. A family of membrane-bound transcription factors, called Sterol Regulatory Element-Binding Proteins (SREBPs), regulates synthesis of cholesterol, fatty acids, and triglycerides. SREBP activation requires SREBP Cleavage Activating Protein (SCAP) that escorts SREBP from the ER-to-Golgi where SREBP is cleaved by Golgi proteases. SCAP then recycles back to the ER for additional rounds of SREBP binding and transport. Multiple mechanisms control SREBP activity, and additional regulation undoubtedly exists. To better understand the SREBP pathway and control of lipid homeostasis, we are studying orthologs of SREBP and SCAP in the fission yeast Schizosaccharomyces pombe, called Sre1 and Scp1.
Our characterization of the fungal SREBP pathway revealed that Sre1 and Scp1 function in an oxygen-responsive pathway. Sre1-Scp1 respond to changes in oxygen-dependent sterol synthesis as an indirect measure of environmental oxygen. Under low oxygen, Sre1 activates a gene expression program that is essential for hypoxic growth. Activation of Sre1 by low oxygen requires processing of this transcription factor in the Golgi through the action of the multi-subunit Golgi Dsc E3 ligase.
- To characterize the function of Dsc E3 ligase in Sre1 proteolysis
- To identify the Sre1 protease(s)
- To identify additional positive and negative regulators of Sre1 activity
Funding: NIH – National Heart, Lung, and Blood Institute, and the Pancreatic Cancer Action Network
- To understand the mechanism for oxygen-dependent regulation of Sre1 by Ofd1
- To understand function of mammalian Ofd1 homolog, OGFOD1
Funding: American Heart Association
- Identifying targets and regulators of CPH2 in C. albicans with the goal of understanding host colonization and developing antifungal therapies.
Funding: NIH – National Institute of Allergy and Infectious Diseases