Cholesterol is an essential component of cell membranes and cells utilize both transcriptional and posttranscriptional mechanisms to regulate cellular sterol homeostasis. In mammals, transcription of genes in cholesterol uptake and synthesis is controlled by the sterol regulatory element binding protein (SREBP) pathway. Cholesterol synthesis is also regulated by sterol-mediated degradation of HMG-CoA reductase, a rate limiting enzyme in this pathway. The goal of my thesis research was to advance our understanding of how cells sense cholesterol and identify new mechanisms utilized by cells to maintain sterol homeostasis.

In my work, I characterized an orthologous SREBP pathway in the fission yeast, S. pombe, and uncovered a new oxygen sensing role for this pathway. Fission yeast SREBP (Sre1) and SREBP cleavage-activating protein (Scap/Scp1) are regulated by oxygen dependent alterations in sterol synthesis and low oxygen activation of Sre1 increases transcription of genes required for adaptation to hypoxia. I also identified the sterol pathway intermediate lanosterol as a low oxygen signal for Sre1 activation and discovered 23 mutations in the sterol sensing domain of Scp1 that constitutively activate Sre1. Lastly, I characterized Dap1 and its human homolog progesterone receptor membrane component 1 (PGRMC1) as cytochrome P450 binding proteins that utilize heme to control activity of two P450 enzymes in sterol synthesis, Cyp51A1 and Cyp61Al. Collectively, these results identified a new link between oxygen sensing and sterol homeostasis and uncovered a heme-dependent posttranscriptional mechanism to regulate sterol synthesis and cytochrome P450 metabolism in yeast and mammals.