David Levin

Research Description

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 two-fold. 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.

Our work centers on the molecular mechanisms involved in the activation and signaling output of two stress-activated MAP kinase (SAPK) pathways — the Cell Wall Integrity (CWI) pathway, which responds to cell wall challenges during growth and morphogenesis, and the High Osmolarity Glycerol (HOG) pathway, which responds to hyper-osmotic stress. We have found in recent studies that, like mammalian SAPK pathways, these two yeast pathways respond to a wide variety of stress conditions in addition to their well-understood functions in the maintenance of the cell wall and osmotic balance. These stresses include DNA damage, metal toxicity, oxidative stress, organic acid stress, and others. We are currently pursuing a very interesting pair of related questions. Specifically, what are the pathways by which such different types of stress stimulate the same SAPKs, and how does their stimulation by these diverse signals result in stress-specific signaling outputs?

Publications

Lee, J., L. Liu, and D. E. Levin (2018). Stressing out or stressing in: intracellular pathways for SAPK activation. Curr. Genet., https://doi.org/10.1007/s00294-018-0898-5

Liu, L. and D. E. Levin (2018). Intracellular mechanism by which genotoxic stress activates yeast SAPK Mpk1. Mol. Biol. Cell., 29:2898-2909.

Lee, J. and D. E. Levin. (2018). Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1. Mol. Biol. Cell., 29:1904-1915.

Lee, J. and D. E. Levin. (2015). Rgc2 regulator of glycerol channel Fps1 functions as a homo- and heterodimer with Rgc1. Euk. Cell, 14:719-725.

Lee, J., W. Reiter, I. Dohnal, C. Gregori, S. Beese-Sims, K. Kuchler, G. Ammerer, and D. E. Levin (2013). MAPK Hog1 closes the S. cerevisiae glycerol channel Fps1 by phosphorylating and displacing its positive regulators. Genes & Dev., 27:2590-2601.

Beese-Sims, S. E., S-J Pan, J. Lee, E. Hwang-Wong, B. P. Cormack, and D. E. Levin. (2012). Mutants in the Candida glabrata glycerols are sensitive to cell wall stress. Euk. Cell, 11:1512-1519.

Levin, D. E. (2011). Regulation of cell wall biogenesis in Saccharomyces cerevisiae: The cell wall integrity signaling pathway. Genetics, 189:1145–1175.

Kim, K-Y and D. E. Levin. (2011). Mpk1 MAPK association with the Paf1 complex blocks Sen1-mediated premature transcription termination. Cell, 144:745–756.

Kim, K-Y, A. W. Truman, S. Caesar, G. Schlenstedt, and D. E. Levin. (2010). Yeast Mpk1 cell wall integrity MAPK regulates nucleocytoplasmic shuttling of the Swi6 transcriptional regulator. Mol. Biol. Cell, 21:1609–1619.

Beese, S. E., T. Negishi, and D. E. Levin. (2009). Identification of positive regulators of the yeast Fps1 glycerol channel. PLoS Genetics, 5: e1000738.

Truman, A. W., K-Y Kim, and D. E. Levin. (2009). Mechanism of Mpk1 MAPK binding to the Swi4 transcription factor and its regulation by a novel caffeine-induced phosphorylation. Mol. Cell. Biol., 29:6449–6461.