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.
Highlights
Within the eukaryotic cell, the endoplasmic reticulum (ER) is a dynamic membrane network involved in many essential cellular processes
We summarize evidence that supports the bi-directional interplay between lipid metabolism and unfolded protein response (UPR-ER) activation in different species with an emphasis on we explore the potential of -omics approaches to delineate how metabolic disturbances might activate the UPR-ER in C. elegans, and how this could deepen our understanding of lipid-disturbance-induced UPR-ER in the pathophysiology of human metabolic diseases
Recent progress has aimed at distinguishing proteotoxicity-induced UPR-ERPT from lipotoxicity-induced UPR-ERLBS, yielding valuable insights into the lipid bilayer stress (LBS)-induced activation mechanism of IRE-1 and the genetic regulation of membrane lipid homeostasis at a molecular level
Summary
The endoplasmic reticulum (ER) is a dynamic membrane network involved in many essential cellular processes. The UPR-ER is composed of three parallel ER stress sensing and transducing branches: the Inositol-Requiring-Enzyme 1α (IRE-1α, known as Endoplasmic Reticulum to Nucleus signaling 1 or ERN1 in mammals) branch [2]; the protein kinase RNA-like ER kinase (PERK; known as human PERK kinase homolog, PEK-1; or Eukaryotic Translation Initiation Factor 2 Alpha Kinase 3 or EIF2AK3) branch [6]; and the Activating Transcription Factor 6 (ATF-6) branch [7] (Figure 1) These three sensors are embedded in the ER membrane with a single-pass transmembrane domain, which connects a luminal sensor domain to a cytosolic effector domain. We summarize evidence that supports the bi-directional interplay between lipid metabolism and UPR-ER activation in different species with an emphasis on we explore the potential of -omics approaches to delineate how metabolic disturbances might activate the UPR-ER in C. elegans, and how this could deepen our understanding of lipid-disturbance-induced UPR-ER in the pathophysiology of human metabolic diseases
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