|Department Affiliations||Cell Biology|
|Rank||Professor, Associate Dean for Graduate Biomedical Education|
|SOM Address||107B Physiology|
To maintain homeostasis, cells must be able to measure the concentration of molecules such as nutrients, chemical reactants, and products. Eukaryotes require environmental oxygen for essential metabolic processes, and thus cells possess mechanisms to sense and adapt to changes in oxygen supply. The hypoxia-inducible factor (HIF) is a key regulator of these adaptive responses in metazoans. Our discovery that the Sterol Regulatory Element Binding Protein (SREBP) is an oxygen-regulated transcription factor established a new paradigm for hypoxic adaptation and revealed new mechanisms for oxygen sensing.
The membrane-bound SREBP transcription factors function as central regulators of lipid homeostasis in mammalian cells by controlling cholesterol and fatty acid synthesis. Our characterization of the SREBP pathway in the fission yeast Schizosaccharomyces pombe demonstrated that yeast SREBP, named Sre1, is an oxygen-regulated transcription factor that mediates adaptation of cells to low oxygen. We extended our findings to the human fungal pathogen Cryptococcus neoformans, showing that oxygen regulation of Sre1 is conserved in this opportunistic pathogen and that the SREBP pathway is required for virulence. Current studies are testing whether oxygen also regulates mammalian SREBP.
Novel oxygen-sensing mechanisms control Sre1 activity. We discovered that a central regulator of Sre1 activity is an oxygen-sensing prolyl hydroxylase Ofd1 and we are investigating the function of its mammalian homolog OGFOD1. We also showed that Sre1 is proteolytically activated by a unique mechanism requiring the Golgi-localized Dsc E3 ligase. This multi-subunit membrane E3 ligase resembles those involved in ER-associated degradation (ERAD) and represents the first candidate machinery for Golgi protein quality control. Our lab addresses these questions of molecular sensing using multi-organismal and multi-disciplinary approaches.
FInally, solid tumors are hypoxic and continued tumor growth requires adaptation to low oxygen supply. Using pancreatic cancer as a model, we are testing whether the SREBP pathway is required for pancreatic tumor growth to determine whether this pathway is a therapeutic target.
• 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. PMID 25918164
• Gong X, Li J, Shao W, Wu J, Qian H, Ren R, Espenshade PJ*, Nieng Y*. 2015. Crystal structure of the WD40 domain of SCAP from fission yeast reveals the molecular basis for SREBP recognition. Cell Research 25:401-11. PMID 25771684
• 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. PMID 24478315
• 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. PMID 23760507
• Cheung R, Espenshade PJ. 2013. Structural requirements for Sterol Regulatory Element-Binding Protein (SREBP) cleavage in fission yeast. J. Biol. Chem. 288:20351-20360. PMID 23729666
• 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. PMID 22833559
• Shao W, Espenshade PJ. 2012. Expanding roles for SREBP in metabolism. Cell Met. 16:414-419. PMID 23000402
• 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. PMID 22086920
• 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. PMID 22017871
• 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. PMID 21481773
• 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. PMID 21504829