Regulation of Sterol Homeostasis

Elevated serum cholesterol is a primary risk factor for heart disease. A negative feedback mechanism prevents cellular cholesterol overaccumulation 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.

Publications:

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.PubMed

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.PubMed

Hughes AL, Stewart EV and Espenshade PJ. 2008. Identification of 23 mutations in fission yeast Scap that constitutively activate SREBP. J. Lipid Research 49:2001-2012.PubMed

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.PubMed

Sehgal A, Hughes BT, Espenshade PJ. 2008. Oxygen-dependent, alternative promoter controls translation of tco1+ in fission yeast. Nucleic Acids Research 36:2024-2031.PubMed

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

Lee H, Bien CM, Hughes AL, Espenshade PJ, Kwon-Chung KJ, Chang YC. 2007. Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans. Mol. Microbiol. 65:1018-1033.PubMed

Hughes AL, Lee CY, Bien CM, Espenshade PJ. 2007. 4-Methyl sterols regulate fission yeast SREBP-Scap under low oxygen and cell stress. J. Biol. Chem. 282:24388-96.PubMed

Chang YC, Bien CM, Lee H, Espenshade PJ, Kwon-Chung KJ. 2007. Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. Mol. Microbiol. 64:614-29.PubMed

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.PubMed

Todd BL, Stewart EV, Burg JS, Hughes AL, Espenshade PJ. 2006. SREBP is a principal regulator of anaerobic gene expression in fission yeast. Mol. Cell. Biol. 26:2817-2831.PubMed