Molekulare Mechanismen des Zwiegesprächs von Proteinumsatz und Membranfluidität

膜的流动性对生命至关重要，并被严格控制在一个狭窄的范围内。复杂生物膜的流动性很大程度上取决于膜脂中饱和和不饱和脂肪酸的比例。尽管脂肪酸去饱和的机制已被深入研究，但膜流动性的分子传感器尚不清楚。利用定量质谱技术，我们将筛选影响体内脂质饱和度的基因，并通过在特定的膜环境中纯化和重构来研究它们在体外作用的机制。我最近确定了内质网（ER）质量控制机制的一个组成部分，作为假定的膜流动性传感器，并可以证明其结合不饱和脂肪酸的能力。这些发现导致了我的假设，即负责内质网衍生蛋白周转的底物谱是由脂肪酸直接调节的，这些机制负责膜流动性稳态。为了验证这一假设，我开发了一种方法来微调细胞脂质组对脂质饱和度的影响，并将量化这些扰动对蛋白质周转和分泌的影响。本研究旨在更好地了解膜脂和蛋白稳态的分子机制及其潜在的分子机制。

Membrane fluidity is essential for life and tightly controlled within a narrow regime. The fluidity of a complex biological membrane is largely dependent on the fraction of saturated and unsaturated fatty acids incorporated into membrane lipids. Even though the mechanisms of fatty acid desaturation have been intensively studied, the molecular sensors of membrane fluidity are not known. Using and quantitative, mass-spectrometry based lipidomics of Saccharomyces cerevisiae, we will screen for genes that affect lipid saturation in vivo and study the mechanism behind their effects in vitro by purification and reconstitution in defined membrane environments. I have recently identified a component of the endoplasmic reticulum (ER) quality control machinery as a putative sensor of membrane fluidity and could demonstrate its capacity to bind unsaturated fatty acids. These findings lead to my hypothesis that the substrate spectrum of the machineries responsible for turnover of ER-derived proteins is directly modulated by fatty acids, and that these mechanisms are responsible for membrane fluidity homeostasis. To test this hypothesis, I have developed methods to fine-tune the cellular lipidome with respect to lipid saturation and will quantify the effects of these pertubations protein turnover and secretion. This proposal aims at a better understanding of the molecular mechanism underlying membrane lipid and protein homeostasis and the underlying molecular mechanisms.