Xu Jiaming, Taubert Stefan
Graduate Program in Cell and Developmental Biology, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Metabolites. 2021 Jan 14;11(1):52. doi: 10.3390/metabo11010052.
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 . 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.
生物膜不仅是分隔细胞和亚细胞结构的重要屏障，还执行其他关键功能，如细胞内和细胞间信号的起始与传播。每个由膜界定的细胞器都有严格调控且定制的膜脂组成，这对其正常功能至关重要。内质网（ER）由一个动态膜网络组成，是蛋白质和脂质合成与修饰所必需的。内质网腔中未折叠蛋白的积累会激活一种适应性应激反应，称为未折叠蛋白反应（UPR-ER）。有趣的是，最近的研究结果表明，脂质紊乱也是UPR-ER的直接激活剂，与蛋白质错误折叠无关。在这里，我们回顾了在遗传上易于处理的模式生物中与蛋白质稳态无关的UPR-ER激活。我们综述了目前关于内质网膜脂组成、其对细胞器功能和UPR-ER激活的影响以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与UPR-ER之间的双向相互作用。我们讨论了最近在确定蛋白质稳态紊乱和脂质双层应激激活UPR-ER的不同各自机制方面取得的进展。最后，我们考虑遗传和代谢紊乱如何可能破坏内质网稳态并激活UPR，并讨论使用组学类型分析将如何导致对这些过程有更全面的见解。
