EukaryoticHopanoids: Deciphering the regulatory network behind unusual lipids in eukaryotes

Eukaryotes use sterols to modulate biophysical properties of cellular membranes, whereas some bacteria produce hopanoids as sterol mimics. Unlike sterols, hopanoids do not require oxygen for their biosynthesis. Interestingly, some eukaryotic organisms populating hypoxic environments, including several species of pathogenic fungi, appear to have acquired squalene-hopene cyclase (SHC), the enzyme responsible for hopanoid production, through horizontal gene transfer. How SHC is "domesticated", and how the regulation of hopanoid and sterol production is coordinated, is unknown. I will probe these fundamental questions using a comparative biology approach. The fission yeast Schizosaccharomyces japonicus relies on SHC to grow anaerobically, whereas its relative, Schizosaccharomyces pombe, is an obligate aerobe lacking SHC. I will use a combination of molecular genetics, cell biology, protein and lipid biochemistry, and next generation sequencing approaches to explain 1) how hopanoid production is regulated; 2) how hopanoids contribute to cellular and organismal physiology in the presence and absence of oxygen; and 3) how S. japonicus balances the production of ergosterol and hopanoids depending on environmental conditions. Understanding how hopanoid synthesis is regulated and how it contributes to cellular physiology may help define new targets for antifungal therapies. It may also become useful in industrial biotechnology applications, for instance to support yeast growth in anoxic environment of bioreactors. Importantly, probing this rich biology will also provide wider insights into the principles of membrane organization and function and shed light on the mechanisms underlying "domestication" of horizontally transferred genes in eukaryotes.