Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease

Abstract

Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)-resident transmembrane protein that senses ER stress and is evolutionarily conserved from yeast to humans. IRE1 possesses both Ser/Thr protein kinase and endoribonuclease (RNase) activities within its cytoplasmic domain and is activated through autophosphorylation and dimerization/oligomerization. It mediates a critical arm of the unfolded protein response to manage ER stress provoked by lumenal overload of unfolded/misfolded proteins. Emerging lines of evidence have revealed that in mammals, IRE1α functions as a multifunctional signal transducer that responds to metabolic cues and nutrient stress conditions, exerting profound and broad effects on metabolic homeostasis. In this review, we cover recent advances in our understanding of how IRE1α integrates a variety of metabolic and stress signals and highlight its tissue-specific or context-dependent metabolic activities. We also discuss how dysregulation of this metabolic stress sensor during handling of excessive nutrients in cells contributes to the progression of obesity and metabolic disorders.

Keywords: ER-associated degradation; IRE1α; X-box–binding protein 1 (XBP1); endoplasmic reticulum stress (ER stress); endoplasmic reticulum to nucleus signaling 1 (Ern1); metabolic inflammation; nutrient sensing; regulated IRE1-dependent decay (RIDD); signal transduction; unfolded protein response (UPR).

Figure 1.

Activation of IRE1α as a metabolic stress sensor. In addition to protein folding overload within the ER lumen, the mammalian ER-localized transmembrane stress sensor IRE1α can also sense the indicated nutrient or metabolic signals that activate its downstream effector activities. As a UPR signal transducer with an N-terminal LD for detecting unfolded/misfolded proteins, IRE1α possesses a cytoplasmic domain with dual kinase/RNase activities. Upon typical ER stress, IRE1α activation involves dimerization/oligomerization and autophosphorylation. Activated IRE1α RNase can catalyze the unconventional splicing of Xbp1 mRNA, removing a 26-nucleotide intron from the unspliced Xbp1 (Xbp1u) mRNA. Subsequently, RNA ligase RtcB-mediated ligation yields the spliced form of Xbp1 (Xbp1s) mRNA and generates a transcriptionally active transcription factor XBP1s to initiate a key UPR gene expression program to cope with ER stress and maintain the homeostatic control of cell proliferation and metabolism. IRE1α can also degrade select sets of mRNAs or pre-miRNAs through a process termed RIDD. In addition, IRE1α can interact with an increasing number of protein partners (indicated by X, Y, and Z) and presumably serves as a signaling platform composed of regulatory factors as well as signaling effectors. Under metabolic stress conditions, IRE1α may act as a multitasked protein machinery that is involved in regulating many aspects of metabolism.

Figure 2.

IRE1α exerts a broad range of tissue- or cell type-specific functions in metabolic organs. IRE1α responds to metabolic cues and nutrient stress signals, exerting broad and profound metabolic effects. In the hypothalamus, IRE1α is implicated in energy balance control and regulation of leptin sensitivity. In pancreatic islets, IRE1α responds to glucose stimulation and acts to control insulin biosynthesis, processing, and secretion, as well as the compensatory proliferation and growth of β-cells in the setting of metabolic ER stress and insulin resistance. In the liver, IRE1α responds to both anabolic and catabolic stimulatory signals and regulates a variety of metabolic pathways in glucose and lipid metabolism as indicated. In adipose tissues, IRE1α performs regulatory functions in adipogenesis, thermogenesis, and metabolic inflammation.

Figure 3.

IRE1α dysregulation links metabolic ER stress to metabolic disorders. Under overnutrition-induced chronic ER stress, IRE1α can hypothetically undergo dysregulated activation arising from intrinsic alterations in its phosphorylation and/or other indicated modifications that may cause aberrant protein complex assembly. IRE1α's conversion from an adaptive activation state to a dysregulated form can result in maladaptive effector outputs, thereby exerting its disruptive actions upon metabolic homeostasis.