Biological membranes are not only essential barriers that separate cellular and subcellular structures, but also perform other critical functions such as the initiation and propagation of intra- and intercellular signals. Each membrane-delineated organelle has a tightly regulated and custom-made membrane lipid composition that is critical for its normal function. The endoplasmic reticulum (ER) consists of a dynamic membrane network that is required for the synthesis and modification of proteins and lipids. The accumulation of unfolded proteins in the ER lumen activates an adaptive stress response known as the unfolded protein response (UPR-ER). Interestingly, recent findings show that lipid perturbation is also a direct activator of the UPR-ER, independent of protein misfolding. Here, we review proteostasis-independent UPR-ER activation in the genetically tractable model organism Caenorhabditis elegans. We review the current knowledge on the membrane lipid composition of the ER, its impact on organelle function and UPR-ER activation, and its potential role in human metabolic diseases. Further, we summarize the bi-directional interplay between lipid metabolism and the UPR-ER. We discuss recent progress identifying the different respective mechanisms by which disturbed proteostasis and lipid bilayer stress activate the UPR-ER. Finally, we consider how genetic and metabolic disturbances may disrupt ER homeostasis and activate the UPR and discuss how using -omics-type analyses will lead to more comprehensive insights into these processes.

中文翻译：

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超越蛋白质稳态：脂质代谢作为内质网稳态的新参与者

生物膜不仅是分隔细胞和亚细胞结构的重要屏障，而且还执行其他关键功能，例如细胞内和细胞间信号的启动和传播。每个膜描绘的细胞器都有严格调节和定制的膜脂成分，这对其正常功能至关重要。内质网 (ER) 由蛋白质和脂质的合成和修饰所需的动态膜网络组成。未折叠蛋白在 ER 腔中的积累会激活适应性应激反应，称为未折叠蛋白反应 (UPR-ER)。有趣的是，最近的研究结果表明，脂质扰动也是 UPR-ER 的直接激活剂，与蛋白质错误折叠无关。在这里，我们回顾了遗传易处理的模式生物秀丽隐杆线虫中与蛋白质稳态无关的 UPR-ER 激活。我们回顾了目前关于 ER 膜脂组成、其对细胞器功能和 UPR-ER 激活的影响及其在人类代谢疾病中的潜在作用的知识。此外，我们总结了脂质代谢和 UPR-ER 之间的双向相互作用。我们讨论了最近的进展，确定了蛋白质稳态紊乱和脂质双层应激激活 UPR-ER 的不同机制。最后，我们考虑遗传和代谢紊乱如何破坏 ER 稳态并激活 UPR，并讨论如何使用组学类型分析来更全面地了解这些过程。