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Regulation of Sterol Homeostasis Elevated serum cholesterol is a primary risk factor for heart disease. A negative feedback mechanism prevents excessive cellular cholesterol accumulation by regulating SREBP, a membrane-bound transcription factor that activates genes required for cholesterol biosynthesis and uptake of cholesterol-rich lipoproteins. We use the genetics of fission yeast as a discovery tool to identify new components of this sterol-sensing pathway in mammalian cells. Oxygen Sensing Our characterization of yeast SREBP and its regulator Scap, called Sre1 and Scp1, revealed that fission yeast SREBP-SCAP function in an oxygen sensing pathway. Sre1-Scp1 monitor 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 anaerobic growth. Recently, we extended these studies to the pathogenic basidiomycete, Cryptococcus neoformans. In this organism, Sre1 also controls adaptation to low oxygen and this gene expression program is required for virulence in a mouse model of infection. Thus, an emerging research focus of the lab is to describe the multiple mechanisms that cells use to sense and respond to changes in oxygen supply. Using this multi-organismal approach, we will identify new regulators of oxygen homeostasis.
Burr R, Stewart EV, Espenshade PJ. 2017. Coordinate regulation of yeast sterol regulatory element-binding protein and Mga2 transcription factors. J Biol Chem. 292:5311-5324
Gong X, Qian H, Shao W, Li J, Wu J, Liu JJ, Li W, Wang HW, Espenshade PJ, Yan N. 2016. Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization. Cell Res. 26:1197-1211.
Hwang J, Ribbens D, Raychaudhuri S, Cairns L, Gu H, Frost A, Urban S, Espenshade PJ. 2016. A Golgi rhomboid protease Rbd2 recruits Cdc48 to cleave yeast SREBP. EMBO J. 35:2332-2349.
Shao W, Machamer CE, Espenshade PJ. 2016. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J. Lipid Res. 57:1564-1573.
Hwang J, Espenshade PJ. 2016. Proximity-dependent biotin labeling in yeast using the engineered ascorbate peroxidase APEX2. Biochem. J. 473:2463-2469.
Burr R, Stewart EV, Shao W, Zhao S, Hannibal-Bach HK, Ejsing CS, Espenshade PJ. 2016. Mga2 transcription factor regulates an oxygen-responsive lipid homeostasis pathway in fission yeast. J. Biol. Chem. 291:12171-12183.
Raychaudhuri S, Espenshade PJ. 2015. Endoplasmic reticulum exit of Golgi-resident defective for SREBP cleavage (Dsc) E3 ligase complex requires its activity. J. Biol. Chem. 290:14430-14440.
Tong Z, Kim MS, Pandey A, Espenshade PJ. 2014. Identification of candidate substrates for the Golgi Tul1 E3 ligase using quantitative diGly proteomics in yeast. Mol. Cell Proteomics 13:2871-82.
Shao W, Espenshade PJ. 2014. Sterol Regulatory Element-binding Protein (SREBP) cleavage regulates Golgi-to-Endoplasmic Reticulum recycling of SREBP Cleavage-activating Protein (SCAP). J. Biol. Chem. 289:7547-7557.
Lloyd SJ, Raychaudhuri S, Espenshade PJ. 2013. Subunit architecture of the Golgi Dsc E3 ligase required for Sterol Regulatory Element-Binding Protein (SREBP) cleavage in fission yeast. J. Biol. Chem. 288:21043-21054.
Ryan CJ, Roguev A, Patrick K, Xu J, Jahari H, Tong Z, Beltrao P, Shales M, Qu H, Collins SR, Kliegman, JI, Jiang L, Kuo D, Tosti E, Kim H, Edelmann W, Keogh M, Greene D, Tang C, Cunningham P, Shokat KM, Cagney G, Svensson JP, Guthrie C, Espenshade PJ, Ideker T, Krogan NJ. 2012. Hierarchical modularity and the evolution of genetic interactomes across species. Mol. Cell. 46:691-704.
Lee CSY, Yeh TL, Hughes BT, Espenshade PJ. 2011. Regulation of the Sre1 hypoxic transcription factor by oxygen-dependent control of DNA binding. Mol. Cell 44:225-234.
Stewart EV, Nwosu CC, Tong Z, Roguev A, Cummins TD, Kim DU, Hayles J, Park HO, Hoe KL, Powell DW, Krogan NJ, Espenshade PJ. 2011. Yeast SREBP cleavage activation requires the Golgi Dsc E3 ligase complex. Mol. Cell 42:160-171.