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Peter Espenshade, Ph.D.

Peter Espenshade, Ph.D.

Academic Titles: 
Associate Dean for Graduate Biomedical Education
Position Title: 
Principal Investigator
443-287-5026 (Office)
443-287-5027 (Lab)
410-955-4129 (Fax)

Department of Cell Biology 
Johns Hopkins University School of Medicine
725 N. Wolfe Street, 107B Physiology
Baltimore, MD 21205

Research Topic: Cellular regulation of cholesterol homeostasis and adaptation to hypoxia

To maintain homeostasis, cells need to measure the concentration of molecules such as nutrients, reactants, and products. Eukaryotic cells, whether single-cell fungi or part of a complex human organ, require environmental oxygen for essential reactions. Consequently, 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-responsive transcription factor in fungi established a new paradigm for hypoxic adaptation and revealed new mechanisms for oxygen sensing.

SREBP transcription factors function as central regulators of lipid homeostasis in mammalian cells by controlling cholesterol and fatty acid synthesis. Our studies 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.

Novel oxygen-sensing mechanisms control Sre1 activity. We discovered that a central regulator of Sre1 activity is an oxygen-sensing prolyl hydroxylase Ofd1 (OGFOD1 in mammals), and 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 and represents the first candidate machinery for Golgi protein quality control.

Lastly, our studies in fission yeast highlighted that lipid synthesis is oxygen-dependent and that cells must adapt under hypoxia to maintain lipid supply. Solid tumors are hypoxic, and continued tumor growth requires lipid 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.

Unified around the central themes of oxygen sensing and regulation of homeostasis, our ongoing and planned research goals are:

1. To define mechanisms for oxygen regulation of SREBP in yeast and humans
2. To identify signaling pathways that regulate cell growth in response to oxygen and lipid supply
3. To identify new regulators of the SREBP family of transcription factors

Research Interest: 
Cellular regulation of cholesterol homeostasis and adaptation to hypoxia
Research Associates and Staff:
Lab Members:
Namesort descending Classification Email Phone
Chiaki Ishida, Ph.D. Postdoctoral Fellow cishida1@jhmi.edu 443-287-5027
Chune Liu, Ph.D. Postdoctoral Fellow cliu117@jhmi.edu 443-287-5027
Shan Zhao Research Technologist szhao6@jhmi.edu 443-287-5027
Stephanie Myers, DVM Student smyers40@jhmi.edu 443-287-5027
Selected Publications:
Gutiérrez MS, Campusano S, González AM, Gómez M, Barahona S, Sepúlveda D, Espenshade PJ, Fernández-Lobato M, Baeza M, Cifuentes V, Alcaíno J. Sterol Regulatory Element-Binding Protein (Sre1) Promotes the Synthesis of Carotenoids and Sterols in Xanthophyllomyces dendrorhous. Front Microbiol. 2019 Mar 29;10:586. doi: 10.3389/fmicb.2019.00586. eCollection 2019.  
Burr R, Stewart EV, Espenshade PJ. 2017. Coordinate regulation of yeast Sterol Regulatory Element-binding Protein (SREBP) and Mga2 transcription factors. J. Biol. Chem. 292:5311-5324. PMCID: PMC5392677
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. PMCID: PMC5090219
Gong X, Qian H, Shao W, Li J, Wu J, Li W, Espenshade PJ*, Nieng Y*. 2016. Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization. Cell Res. 26:1197-1211. *Corresponding authors. PMCID: PMC5099872
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.
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. 2016 Jun 3;291(23):12171-83. doi: 10.1074/jbc.M116.723650. Epub 2016 Apr 6.
Shao W, Espenshade PJ. 2015. Sugar Makes Fat by Talking to SCAP. Cancer Cell. 2015 Nov 9;28(5):548-9. doi: 10.1016/j.ccell.2015.10.011.
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. 290:14430-40.
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. PMCID: PMC4387560  
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. PMCID: PMC4223478
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. 288:21043-54.
Cheung R, Espenshade PJ. 2013. Structural requirements for Sterol Regulatory Element- Binding Protein (SREBP) cleavage in fission yeast. J. Biol. Chem. 288:20351-60.
Espenshade PJ. 2013. Cholesterol Synthesis and Regulation. In: Lennarz, W.J. and Lane, M.D. (eds.) The Encyclopedia of Biological Chemistry, Vol. 3, pp. 516-520. Waltham, MA: Academic Press.
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.
Shao W, Espenshade PJ. 2012. Expanding roles for SREBP in metabolism. Cell Met. 16:414-419.
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.
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. 287:672-81.
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. 286:27139-46.
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.
Porter JR, Burg JS, Espenshade PJ, Iglesias PA. 2010. Ergosterol regulates SREBP cleavage in fission yeast. J. Biol. Chem. 285:41051-61.
Bien CM and Espenshade PJ. 2010. SREBP in fungi - Hypoxic transcription factors linked to pathogenesis. Eukaryotic Cell 9:352-9.
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.
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.
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.
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.
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.