Cellular lipid homeostasis is required to maintain bilayer fluidity, membrane impermeability, and organelle identity. Disturbances in systemic lipid homeostasis lie at the core of the pathologies for both coronary artery disease and obesity related type II diabetes. The long-term goal of this research is to translate knowledge of cellular regulatory events to that of the whole organism and to advance our understanding of these increasingly widespread diseases. As a first step toward this goal, we will use cholesterol as a model lipid to understand how cells measure levels of these largely insoluble molecules and in turn modulate their production. Cholesterol homeostasis in mammalian cells is regulated by a feedback mechanism that monitors the level of cholesterol in membranes and alters transcription of genes required for cholesterol supply. Transcription of these genes is controlled by the ER membrane-bound transcription factor called SREBP that is activated and released from the membrane by proteolysis in sterol-depleted cells. To accelerate discovery of sterol homeostasis regulators, we are studying the SREBP pathway in the fission yeast Schizosaccharomyces pombe. Yeast SREBP, called Sre1, functions in a new oxygen sensing pathway that mediates adaptation of cells to low oxygen. Interestingly, sterols regulate Sre1 activity through a novel mechanism in fission yeast, and evidence also indicates that Sre1 cleavage is mediated by a unique proteolytic system. In this project, a combination of genetic, molecular, and biochemical approaches will be used to accomplish the following specific aims: 1) To identify genes required for Sre1 cleavage using a genetic selection;2) To define the machinery for Sre1 cleavage;and 3) To define the mechanism of sterol-regulated Sre1 cleavage. The long-term goal of this project is to use S. pombe as a genetic model to understand how cells measure levels of insoluble, membrane-embedded cholesterol. The expectation is that these studies will describe new mechanisms for lipid sensing and proteolysis that will advance our understanding of the mammalia SREBP pathway and eukaryotic cell biology.

Public Health Relevance

Heart disease is a leading killer of adults in the United States. Proper regulation of cellular cholesterol homeostasis is integral to cardiovascular health. In this project, we will use yeast as a genetic model organism to define new mechanisms for regulation of cholesterol homeostasis with the goal of identifying improved therapeutic strategies for lowering serum cholesterol and preventing heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Liu, Lijuan
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Johns Hopkins University
Anatomy/Cell Biology
Schools of Medicine
United States
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Burr, Risa; Espenshade, Peter J (2018) Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development. Semin Cell Dev Biol 81:110-120
Burr, Risa; Stewart, Emerson V; Espenshade, Peter J (2017) Coordinate Regulation of Yeast Sterol Regulatory Element-binding Protein (SREBP) and Mga2 Transcription Factors. J Biol Chem 292:5311-5324
Clasen, Sara J; Shao, Wei; Gu, He et al. (2017) Prolyl dihydroxylation of unassembled uS12/Rps23 regulates fungal hypoxic adaptation. Elife 6:
Burr, Risa; Ribbens, Diedre; Raychaudhuri, Sumana et al. (2017) Dsc E3 ligase localization to the Golgi requires the ATPase Cdc48 and cofactor Ufd1 for activation of sterol regulatory element-binding protein in fission yeast. J Biol Chem 292:16333-16350
Burr, Risa; Stewart, Emerson V; Shao, Wei et al. (2016) Mga2 Transcription Factor Regulates an Oxygen-responsive Lipid Homeostasis Pathway in Fission Yeast. J Biol Chem 291:12171-83
Shao, Wei; Machamer, Carolyn E; Espenshade, Peter J (2016) Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res 57:1564-73
Hwang, Jiwon; Espenshade, Peter J (2016) Proximity-dependent biotin labelling in yeast using the engineered ascorbate peroxidase APEX2. Biochem J 473:2463-9
Hwang, Jiwon; Ribbens, Diedre; Raychaudhuri, Sumana et al. (2016) A Golgi rhomboid protease Rbd2 recruits Cdc48 to cleave yeast SREBP. EMBO J 35:2332-2349
Gong, Xin; Qian, Hongwu; Shao, Wei et al. (2016) Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization. Cell Res 26:1197-1211
Shao, Wei; Espenshade, Peter J (2015) Sugar Makes Fat by Talking to SCAP. Cancer Cell 28:548-549

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