Peter Espenshade, Ph.D.

Professor

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

Website

Academic Titles

Professor, Associate Dean for Graduate Biomedical Education

Research Topic

Cellular regulation of cholesterol homeostasis and adaptation to hypoxia

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

Biosketch

Lab Members

Name Classification Email Phone
Casie Kubota Student ckubota1@jhmi.edu 443-287-5027
Chiaki Ishida, Ph.D. Postdoctoral Fellow cishida1@jhmi.edu 443-287-5027
Deb Mukhopadhyay Research Specialist dmukhop1@jhmi.edu 443-287-5027
Josh Laffin Student jlaffin1@jhmi.edu 443-287-5027
Mikayla Chen Student mchen165@jhmi.edu
Rohan Panaparambil Student rohan@jhmi.edu 410-614-3382
Shan Zhao Research Technologist szhao6@jhmi.edu 443-287-5027
Skyler Lemmon Student slemmon2@jhmi.edu

Publications

  • Shao W, Hwang J, Liu C, Mukhopadhyay D, Zhao S, Shen MC, Alpergin ESS, Wolfgang MJ, Farber SA, Espenshade PJ. Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor. J Biol Chem. 2020 Oct 27:jbc.RA120.015238. doi: 10.1074/jbc.RA120.015238. Online ahead of print.
  • Esquejo RM, Roqueta-Rivera M, Shao W, Phelan PE, Seneviratne U, Am Ende CW, Hershberger PM, Machamer CE, Espenshade PJ, Osborne TF. Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum. Cell Chem Biol. 2020 Oct 20:S2451-9456(20)30382-2. doi: 10.1016/j.chembiol.2020.10.003. Online ahead of print.

  • 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.

  • Hwang J, Espenshade PJ. 2016. Proximity-dependent biotin labeling in yeast using the engineered ascorbate peroxidase APEX2. Biochem J. 473:2463-2469.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • Shao W, Espenshade PJ. 2012. Expanding roles for SREBP in metabolism. Cell Met. 16:414-419.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

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

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

  • 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.

  • 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.

  • 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.

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