Expertise in stress signaling and cell wall biogenesis in fungi.
We use baker’s yeast, Saccharomyces cerevisiae, as a model genetic organism in which to study the molecular mechanisms of stress signaling. The biomedical relevance of our work is twofold. First, we seek to identify novel aspects of signal transduction that are evolutionarily conserved with humans and therefore tell us something about our own biology that may be useful in the treatment of disease. Second, when we identify aspects or components of signaling pathways that are unique to fungi, these often represent potential targets for antifungal drug discovery.
One project concerns the dissection of the Cell Wall Integrity (CWI) signaling pathway, which detects and responds to cell wall stress during growth and morphogenesis. Because animal cells lack cell walls, this structure is an attractive drug target in fungal pathogens. Disruption of the fungal cell wall results in cell lysis. The CWI pathway uses a set of cell surface sensors that are connected to a small G-protein, which activates signaling through a MAP kinase cascade. We have found in recent studies that, in addition to its catalytic activity as a protein kinase, the MAP kinase of the CWI pathway has a previously unknown non-catalytic function in the control of transcription elongation. We found that the basal expression of many stress-induced genes is minimized through premature transcription termination (or attenuation) shortly after initiation. The non-catalytic function of the MAP kinase under stress conditions is to prevent transcription attenuation through its interaction with the transcription elongation complex. This mechanism appears to be evolutionarily conserved in humans and may offer a new approach to therapeutic gene silencing.
A second project exploits the need of fungal cells to maintain osmotic homeostasis through the regulation of intracellular glycerol concentration. We have identified a pair of genes, named RGC1 and RGC2 (for Regulators of the Glycerol Channel) whose function is to control the activity of the Fps1 glycerol channel, which acts as a plasma membrane vent that decreases turgor pressure by releasing glycerol from the cell. The fungal kingdom is replete with members of the Rgc family of proteins, but they have not been found in metazoan organisms. For this reason, and because mutants in these genes undergo cell lysis as a result of excess turgor pressure, the Rgc proteins may be suitable antifungal targets. Current studies are centered on understanding the biochemical function of Rgc1/2 and their mode of regulation in response to osmotic stress.
- Professor, Microbiology, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Professor, Molecular & Cell Biology, Boston University Henry M. Goldman School of Dental Medicine
- University of California, Berkeley, PhD
- University of Massachusetts Amherst, BS
- Published on 5/29/2015
Lee J, Levin DE. Rgc2 Regulator of Glycerol Channel Fps1 Functions as a Homo- and Heterodimer with Rgc1. Eukaryot Cell. 2015 Jul; 14(7):719-25. PMID: 26024902.
- Published on 12/1/2013
Lee J, Reiter W, Dohnal I, Gregori C, Beese-Sims S, Kuchler K, Ammerer G, Levin DE. MAPK Hog1 closes the S. cerevisiae glycerol channel Fps1 by phosphorylating and displacing its positive regulators. Genes Dev. 2013 Dec 1; 27(23):2590-601. PMID: 24298058.
- Published on 10/19/2012
Beese-Sims SE, Pan SJ, Lee J, Hwang-Wong E, Cormack BP, Levin DE. Mutants in the Candida glabrata glycerol channels are sensitized to cell wall stress. Eukaryot Cell. 2012 Dec; 11(12):1512-9. PMID: 23087370.
- Published on 12/1/2011
Levin DE. Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics. 2011 Dec; 189(4):1145-75. PMID: 22174182.
- Published on 10/26/2011
Beese-Sims SE, Lee J, Levin DE. Yeast Fps1 glycerol facilitator functions as a homotetramer. Yeast. 2011 Dec; 28(12):815-9. PMID: 22030956.
- Published on 3/4/2011
Kim KY, Levin DE. Mpk1 MAPK association with the Paf1 complex blocks Sen1-mediated premature transcription termination. Cell. 2011 Mar 4; 144(5):745-56. PMID: 21376235.
- Published on 8/1/2010
Kim KY, Levin DE. Transcriptional reporters for genes activated by cell wall stress through a non-catalytic mechanism involving Mpk1 and SBF. Yeast. 2010 Aug; 27(8):541-8. PMID: 20641022.
- Published on 3/10/2010
Kim KY, Truman AW, Caesar S, Schlenstedt G, Levin DE. Yeast Mpk1 cell wall integrity mitogen-activated protein kinase regulates nucleocytoplasmic shuttling of the Swi6 transcriptional regulator. Mol Biol Cell. 2010 May 1; 21(9):1609-19. PMID: 20219973.
- Published on 11/26/2009
Beese SE, Negishi T, Levin DE. Identification of positive regulators of the yeast fps1 glycerol channel. PLoS Genet. 2009 Nov; 5(11):e1000738. PMID: 19956799.
- Published on 10/5/2009
Truman AW, Kim KY, Levin DE. Mechanism of Mpk1 mitogen-activated protein kinase binding to the Swi4 transcription factor and its regulation by a novel caffeine-induced phosphorylation. Mol Cell Biol. 2009 Dec; 29(24):6449-61. PMID: 19805511.
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