Our characterization of the yeast SREBP, Sre1, revealed that fission yeast SREBP-SCAP function in an oxygen sensing pathway. Sre1-Scp1 monitor changes in oxygen-dependent sterol synthesis as an indirect measure of environmental oxygen. Under low oxygen, Sre1 activates a gene expression program that is essential for anaerobic growth. In addition, we discovered that oxygen regulates Sre1 at a second point through the prolyl hydroxylase Ofd1 and its negative regulator Nro1. Ofd1-Nro1 function to control the oxygen-dependent stability of active Sre1 that has been released from the membrane by proteolysis.
Current fission yeast projects include:
- Understanding oxygen-dependent regulation of Sre1 by Ofd1
- To determine the machinery and mechanism of Sre1 proteolysis
We extended the study of Sre1 to the pathogenic basidiomycete, Cryptococcus neoformans in collaboration with Dr. June Kwon-Chung at the NIH. In this organism, Sre1 also controls adaptation to low oxygen and this gene expression program is required for virulence in a mouse model of infection. Recently, identical results were found by others in studies with the fungal pathogen Aspergillus fumigatus. Collectively, these studies identify the Sre1 pathway as a therapeutic target for cryptococcosis and suggest that Sre1 inhibitors may have broad anti-fungal application.
Current C. neoformans projects include:
- Describing the low oxygen gene expression programs controlled by Sre1 in C. neoformans
- Understanding the requirement of Sre1 for C. neoformans virulence with the goal of developing therapies for cryptococcosis
Thus, an emerging research focus of the lab is to describe the multiple mechanisms that cells use to sense and respond to changes in oxygen supply. Using this multi-organismal approach, we will identify new regulators of oxygen homeostasis.