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. We are investigating the function of two new hypoxic regulators using mouse knockout technology. Through this multi-organismal approach, we will identify new regulators of oxygen homeostasis.

Select publications

  1.     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 In press.

  2.     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.

  3.     Porter JR, Burg JS, Espenshade PJ, Iglesias PA. 2010. Ergosterol regulates SREBP cleavage in fission yeast. J. Biol. Chem. 285:41051-61.

  4.     Bien CM and Espenshade PJ. 2010. SREBP in fungi - Hypoxic transcription factors linked to pathogenesis. Eukaryotic Cell. 9:352-9.

  5.     Osborne TO and Espenshade PJ. 2009. Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long strange tRIP it’s been. Genes and Dev. 23: 2578-2591.

  6.     Bien CM, Chang YC, Nes WD, Kwon-Chung KJ, and Espenshade PJ. 2009. C. neoformans Site-2 protease is required for virulence and survival in the presence of azole drugs. Mol. Microbiol. 74:672-690.

  7.     Lee CY, Stewart EV, Hughes BT and Espenshade PJ. 2009. Oxygen-dependent binding of Nro1 to the prolyl hydroxylase Ofd1 regulates SREBP degradation in yeast. EMBO J. 28:135-43.

  8.     Burg JS, Powell DW, Chai R, Hughes AL, Link AJ and Espenshade PJ. 2008. Insig regulates HMG-CoA reductase by controlling enzyme phosphorylation in fission yeast. Cell Metabolism 8:522-31.

  9.     Hughes BT and Espenshade PJ. 2008. Oxygen-regulated degradation of fission yeast SREBP by Ofd1, a prolyl hydroxylase family member. EMBO J. 27:1491-1501.

10.     Sehgal A, Lee CY, Espenshade PJ. 2007. SREBP controls oxygen-dependent mobilization of retrotransposons in fission yeast. PLoS Genet. 3:1389-1396.

11.     Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ. 2007. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes . Cell Metabolism 5:143-149.

12.     Hughes AL, Todd BL, Espenshade PJ. 2005. SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120:831-842.