EukaryoticHopanoids: Deciphering the regulatory network behind unusual lipids in eukaryotes

真核生物使用甾醇来调节细胞膜的生物物理性质，而一些细菌产生类Hopanoids作为甾醇模拟物。与甾醇不同，类Hopanoids的生物合成不需要氧气。有趣的是，一些生活在低氧环境中的真核生物，包括几种致病真菌，似乎通过水平基因转移获得了角鲨烯-霍烯环化酶（SHC），这种酶负责hopanoid的产生。SHC是如何被“驯化”的，以及如何协调对hopanoid和固醇产生的调节，尚不清楚。我将用比较生物学的方法来探讨这些基本问题。裂殖酵母裂殖酵母依赖于SHC厌氧生长，而它的亲戚粟酒裂殖酵母是一种缺乏SHC的专性需氧菌。我将使用分子遗传学，细胞生物学，蛋白质和脂质生物化学，以及下一代测序方法的组合来解释1）hopanoid生产是如何调节的; 2）hopanoid如何在存在和不存在氧气的情况下对细胞和生物体生理学做出贡献;以及3）S。根据环境条件，麦角甾醇和类Hopanoids的生产平衡。了解hopanoid合成是如何调节的，以及它如何有助于细胞生理学，可能有助于确定抗真菌治疗的新靶点。它也可能在工业生物技术应用中变得有用，例如支持酵母在生物反应器的缺氧环境中生长。重要的是，探索这种丰富的生物学也将为膜组织和功能的原理提供更广泛的见解，并阐明真核生物中水平转移基因的“驯化”机制。

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.