Faculty & Research
Associate Dean for Graduate Biomedical Education
|School of Medicine Address||Johns Hopkins University School of Medicine|
725 N. Wolfe St., 107B Physiology
Baltimore MD 21205
|Link to Lab Homepage|
Research Topic: Mechanisms of Molecular Sensing
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.
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.
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.
Brookheart RT, Lee CY, Espenshade PJ. 2014. Casein kinase 1 regulates sterol regulatory element-binding protein (SREBP) to control sterol homeostasis. J. Biol. Chem. 289:2725-2735.
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.
Cheung R, Espenshade PJ. 2013. Structural requirements for Sterol Regulatory Element-Binding Protein (SREBP) cleavage in fission yeast. J. Biol. Chem. 288:20351-20360.
Porter JR, Lee CSY, Espenshade PJ, Iglesias PA. 2012. Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA binding and degradation. Mol. Biol. Cell 23:3764-3774.
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.
Porter JR, Burg JS, Espenshade PJ, Iglesias PA. 2012. Identifying a static nonlinear structure in a biological system using noisy, sparse data. J. Theoretical Biol. 300:232-241.
Stewart EV, Lloyd SJ, Burg JS, Nwosu CC, Lintner RE, Daza R, Russ C, Ponchner K, Nusbaum C, Espenshade PJ. 2011. Yeast SREBP cleavage requires Cdc48 and Dsc5, a ubiquitin regulatory X domain-containing subunit of the Golgi Dsc E3 ligase. J. Biol. Chem. 287:672-681.
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.
Burg JS, Espenshade PJ. 2011. Glucose controls phosphoregulation of HMG-COA reductase through the PP2A-related phosphatase Ppe1 and Insig in fission yeast. J. Biol. Chem. 286:27139-27146.
Yeh TL, Lee CSY, Amzel LM, Espenshade PJ and Bianchet MB. 2011. The hypoxic regulator of sterol synthesis Nro1 is a nuclear import adaptor. Structure 19:503-514.
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.