High-Profile Paper Solves Decades-Old Mystery about Stress Signals

Dr. David Levin
Dr. David Levin

Boston University Henry M. Goldman School of Dental Medicine (GSDM) Professor and Chair of the Department of Molecular & Cell Biology Dr. David Levin’s laboratory published a paper the first week of December in the high-profile journal, Genes & Development.

The paper, “MAPK Hog1 closes the S. cerevisiae glycerol channel Fps1 by phosphorylating and displacing its positive regulators,” resulted from a collaboration between Dr. Levin, first author, and GSDM Post-doctoral Associate Dr. Jongmin Lee, and researchers at two laboratories at the University of Vienna, Austria.

Their objective was to understand the molecular details of how fungal cells respond to hyperosmotic stress. The results include implications for anti-fungal drug development.

Maintaining proper osmotic balance is critical to the survival of fungal cells. Many fungal species respond to increases in external osmolarity by increasing their internal glycerol levels. Glycerol accumulation is controlled by the MAP kinase Hog1 (for High Osmolarity Glycerol response) and involves two major aspects—increased glycerol production and decreased glycerol efflux through the glycerol channel Fps1. However, the mechanism by which Hog1 inhibits glycerol movement through Fps1 has remained a mystery for nearly 20 years.

The researchers identified in a previous study a pair of redundant positive regulators of Fps1, called Rgc1 and Rgc2 (for Regulators of the Glycerol Channel), which are important for preventing excessive glycerol accumulation that would otherwise cause the cells to burst. They also had reason to believe that Hog1 might regulate Fps1 by inhibiting a function of Rgc1 and Rgc2.

“The significance of this study is two-fold,” said Dr. Levin. “First, it solves a decades-old mystery about how a stress signal is converted to a physiologic response. Second, it suggests a new approach to the development of anti-fungal therapeutics.”

The study addressed the questions of how Hog1 and Rgc1/2 control the glycerol channel. They found that Rgc1/2 maintains Fps1 in an open (active) state by binding to its C-terminal domain (see photo). Their work also revealed an excellent regulatory mechanism in which activated Hog1 binds to the N-terminal domain of Fps1, which serves as a platform for Hog1 phosphorylation of Rgc1 and Rgc2. This drives the eviction of Rgc1/2 from Fps1, resulting in channel closure and consequent glycerol accumulation. Their study suggests a novel approach to anti-fungal drug development centered on the inhibition of glycerol efflux through Fps1.

“This was a very technically challenging study that was expertly executed by Dr. Jongmin Lee in a collaborative effort with two labs in Vienna, Austria, using state-of-the-art methodologies,” said Dr. Levin. “The result was a magnificently detailed mechanistic understanding of this stress response.”