Nutritional genomics and molecular responses to changes in nutrient status.
The Eide lab is addressing a basic question in biology, i.e. how do cells deal with constantly changing nutrient availability? This is a fundamental issue for all organisms including free-living and pathogenic microbes, as well as multicellular organisms such as plants and mammals. Most of our studies are focused on zinc, an essential metal nutrient, and the yeast Saccharomyces cerevisiae. This simple eukaryote is a great model for studying many important processes including how cells respond to nutrient stress.
The Zap1 transcription factor of S. cerevisiae is the key player in zinc-deficient cells. Using transcriptome profiling and other approaches, we discovered that Zap1 induces expression of more than 80 genes in zinc-limited cells and represses over 30 other genes. This collection of Zap1-regulated genes is providing new insights into how cells respond to zinc deficiency. Strategies of stress response include up-regulating zinc uptake transporters in the plasma membrane and transporters that mobilize intracellular stores of zinc. In addition, transporters that move zinc into organelles such as the endoplasmic reticulum are also induced. Collectively, we refer to these as “homeostatic” responses because they help maintain zinc levels within the cell. We have also discovered a number of other responses that play “adaptive” roles. These adaptive responses aid cell growth under conditions of zinc deficiency and include remodeling of glucose metabolism and increasing oxidative stress tolerance. More recently, we have found that zinc-limited cells face a crisis of misfolded proteins and we are studying how they deal with that disruption. Altogether, we have characterized the role of about 25 of the more than 100 Zap1 target genes. Much of our future work will be directed toward understanding the role of the other ~80 Zap1 targets. This analysis is giving us a very complete picture of how cells of all organisms deal with the stress of nutrient deficiency.
Transcription factors and transporters in zinc homeostasis: lessons learned from fungi. Eide DJ. Crit Rev Biochem Mol Biol. 55:88-110 (2020).
Bucci, M., Weisenhorn, E., Haws, S., Yao, Z., Zimmerman, G., Gannon, M., Taggart, J., Lee, T., Klionsky, D.J., Russell, J., Coon J., and Eide, D.J. An autophagy-independent role for ATG41 in sulfur metabolism during zinc deficiency. Genetics, 208:1115-30 (2018).
Wang, Y, Weisenhorn, E., MacDiarmid, C., Andreini, C., Bucci, M., Taggart, J., Banci, L., Russell, J., Coon, J.J., and Eide, D.J. The cellular economy of the Saccharomyces cerevisiae zinc proteome. Metallomics 10: 1755-1776 (2018)
Taggart, J., MacDiarmid, C., Haws, S., and Eide, D.J. Zap1-dependent transcription from an alternative upstream promoter controls translation of RTC4 mRNA in zinc-deficient Saccharomyces cerevisiae. Mol. Microbiol. 106:678-89 (2017).
Carvalho, S., Barreira, R., Shawki, A., Castro, H., Lamy, M., Eide, D.J., Costa, V., Mackenzie, B., Tomas, A. LiZIP3 is a cellular zinc transporter that mediates the tightly regulated import of zinc in Leishmania infantum parasites. Mol. Microbiol. 96:581-95 (2015).
MacDiarmid, C., Taggart, J., Kerdsomboon, K., Kubisiak, M., Panasharoen, S., Schelble, K., and Eide, D.J. Peroxiredoxin chaperone function is critical for protein homeostasis in zinc-deficient yeast. J. Biol. Chem. 288, 31313-31327 (2013).
Jeong, J. and Eide, D. The SLC39 family of zinc transporters. Molecular Aspects of Medicine 34: 612-619 (2013).
Jeong, J., Walker, J. M., Wang, F., Park, J. G., Palmer, A. E., Giunta, C., Rohrbach, M., Steinmann, B., and Eide, D. Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers-Danlos Syndrome. Proc. Natl. Acad. Sci. USA, 109(51):E3530-8 (2012)
North, M., Steffen, J., Loguinov, V., Zimmerman, G., Vulpe, C., and Eide, D. Genome-wide functional profiling identifies genes and processes important for zinc-limited growth to Saccharomyces cerevisiae. PLoS Genetics 8: e1002699 (2012).
Frey, A.G. and Eide, D. J. The roles of Zap1’s two activation domains in the response to zinc deficiency in Saccharomyces cerevisiae. J. Biol. Chem. 286: 6844-6854 (2011).
Frey, A., Bird, A., Evans-Galea, M., Blankman, E., Winge, D., and Eide, D. Zinc-regulated DNA binding of the yeast Zap1 zinc-responsive activator. PLoS One 6:e22535 (2011).