The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1

University of Santiago, Chile, CiudadSantiago, Santiago Metropolitan, Chile
Physiological Reviews (Impact Factor: 27.32). 10/2011; 91(4):1219-43. DOI: 10.1152/physrev.00001.2011
Source: PubMed


Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

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Article: The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1

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    • "The liberated N-terminal cytoplasmic domain is transported into nuclei to activate UPR target genes. Inositol-requiring enzyme 1 is a type I ER-resident transmembrane protein with an ER luminal dimerization and a cytoplasmic domain with Ser/Thr kinase and endonuclease activities (Hetz et al., 2011). ER stress allows IRE1 to autophosphorylate the kinase domain through dimerization and thereby activate the ribonuclease domain. "
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    • "These responses include transcriptional up-regulation of UPR target genes, global cell translation attenuation, and activation of ER-associated degradation pathways. If the imbalance is not rectified, then the UPR switches from being pro-survival to eliciting an apoptotic response (Zhang & Kaufman, 2008; Hetz et al, 2011; Walter & Ron, 2011). There are three sensor/ transducer proteins: Ire1, PERK, and Atf6, that are critical for initiating mammalian UPR cell signaling and give rise to three separate branches of the response. "
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    ABSTRACT: Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein-folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X-ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
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    • "IRE1/XBP-1 has been shown to regulate a variety of genes in various cell types in response to ER stress, mostly related to ER function and the secretory pathway, although the target genes vary depending on the cell type and nature of the stress stimuli [31]. In the proinsulin C96Y-GFP model of ER stress numerous genes related to ER function, the secretory pathway and ER-associated degradation are increased. "
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