Department of Biology, Ball State University, Muncie, Indiana, USA.
Department of Biology, Ball State University, Muncie, Indiana, USA.
J Biol Chem. 2023 Aug;299(8):104939. doi: 10.1016/j.jbc.2023.104939. Epub 2023 Jun 17.
The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation of Deg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, in Saccharomyces cerevisiae. This screen revealed that INO4 is required for efficient Deg1-Sec62 degradation. INO4 encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis. Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect in ino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases by INO4 deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Loss of INO4 sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.
脂质动态平衡与蛋白质动态平衡（蛋白质稳态）之间的关系非常复杂，目前尚未完全阐明。我们在酿酒酵母中进行了一项筛选实验，以寻找降解 Deg1-Sec62 的必需基因，Deg1-Sec62 是内质网（ER）泛素连接酶 Hrd1 异常易位相关底物的模型。该筛选实验表明，INO4 是 Deg1-Sec62 有效降解所必需的。INO4 编码 Ino2/Ino4 异二聚体转录因子的一个亚基，该转录因子调节参与脂质生物合成的基因表达。编码几种参与磷脂和固醇生物合成的酶的基因突变也会损害 Deg1-Sec62 的降解。INO4 缺失酵母中的降解缺陷可以通过补充由 Ino2/Ino4 靶标介导的合成和摄取的代谢物来挽救。INO4 缺失稳定了一组 Hrd1 和 Doa10 ER 泛素连接酶的底物，表明 ER 蛋白质量控制通常对脂质动态平衡的破坏很敏感。INO4 的缺失使酵母对蛋白毒性应激敏感，这表明脂质动态平衡对维持蛋白质稳态有广泛的需求。深入了解脂质动态平衡与蛋白质动态平衡之间的动态关系，可能有助于更好地理解和治疗与改变脂质生物合成相关的几种人类疾病。
