Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Abstract

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.

Keywords: endoplasmic reticulum; lipid bilayer stress; lipidomics; phosphatidylcholine; unfolded protein response; unsaturated fatty acid.

Figure 1

Overview of the canonical endoplasmic reticulum unfolded protein response (UPR-ER) pathways. In higher eukaryotes, upon sensing misfolded proteins by HSP-4/BiP, the three UPR-ER branches—IRE-1α, PEK-1, and ATF-6—are activated to mount distinct and collective downstream transcriptional and translational programs to promote protein folding, processing, and secretion, thereby reducing the load of misfolded proteins in the ER lumen and alleviating ER stress. Abbreviations: ATF-4: Activating Transcription Factor 4; ATF-6: Activating Transcription Factor 6; eIF2α: Eukaryotic Initiation Factor 2α; HSP-4/BiP: heat shock protein 4/ Binding immunoglobulin protein; IRE-1α: Inositol-Requiring-Enzyme 1α; PEK-1: human PERK kinase homolog; UPR: unfolded protein response; xbp-1: X-box Binding Protein homolog 1. (Figure created with Biorender.com, Toronto, ON, Canada).

Figure 2

Overview of the bidirectional interplay between lipid metabolism and the IRE-1 branch of the UPR-ER in Caenorhabditis elegans. Disturbed ER membrane lipid composition is caused by the loss of mdt-15 or fat-6/7, which cause increased FA saturation, or by the loss of mdt-15, sams-1, pcyt-1, or pmt-2, which cause disturbed PC/PE ratios. All these disturbances are direct triggers for IRE-1 activation, i.e., independent of protein misfolding. Activated IRE-1 upregulates compensatory genes, which remodel lipid metabolism and restore a proper lipid environment in the ER. Genes colored in red have been experimentally shown to cause IRE-1 activation in C. elegans when inactivated. Abbreviations: atgl-1: adipose triglyceride lipase; cept-1: choline/ethanolaminephosphotransferase; FA: fatty acid; fat-6/-7: fatty acid desaturase 6/7; hsp-4: heat shock protein 4; IRE-1: IRE1 kinase related; MDT-15: mediator 15; NHR-49: nuclear hormone receptor 49; PC: phosphatidylcholine; pcyt-1: phosphocholine cytidylyltransferase; PE: phosphatidylethanolamine; PI: phosphatidylinositol; pmt-2: phosphoethanolamine methyltransferase; PS: phosphatidylserine; sams-1: S-adenosyl methionine synthetase; SBP-1: sterol regulatory element binding protein; XBP-1: X-box binding protein homolog. (Some parts of the image were created with BioRender.com, Toronto, ON, Canada).

Figure 3

Overview of lipid synthesis pathways in C. elegans (adapted with permission from [143]). Genes colored in red are known to induce the UPR-ER when inactivated. Abbreviations: CDP-Cho: cytidine diphosphate choline; CDP-DAG: cytidine diphosphate diacylglycerol; CL: cardiolipin; CoA: coenzyme A; DAG: diacylglycerol; elo-1/-2: fatty acid elongation; Etn: ethanolamine; FA: fatty acid; fah-1: fumarylacetoacetate hydrolase; fat-6/-7: fatty acid desaturase 6/7; G3P: glucose-3 phosphate; hgo-1: homogentisate 1,2-dioxygenase; HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A; hmgr-1: hydroxymethylglutaryl-CoA reductase; hmgs-1: hydroxymethylglutaryl-CoA synthase; LPA: lysophosphatidic acid; lpin-1: lipin (mammalian lipodystrophy associated) homolog; PA: phosphatidic acid; PC: phosphatidylcholine; PE: phosphatidylethanolamine; P-Etn: phosphoethanolamine; PG: phosphatidylglycerol; PI: phosphatidylinositol; pmt-2: phosphoethanolamine methyltransferase; PP: pyrophosphate; PS: phosphatidylserine; Ser: serine; SAM: S-adenosyl methionine; sams-1: S-adenosyl methionine synthetase; TAG: triacylglycerol. (Created with BioRender.com, Toronto, ON, Canada).