Structural and molecular bases to IRE1 activity modulation

2021 ◽  
Vol 478 (15) ◽  
pp. 2953-2975
Author(s):  
Timothy Langlais ◽  
Diana Pelizzari-Raymundo ◽  
Sayyed Jalil Mahdizadeh ◽  
Nicolas Gouault ◽  
Francois Carreaux ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
Stress Sensors ◽  
Evolutionarily Conserved ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Molecular Bases

The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

scholarly journals An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

2005 ◽  
Vol 391 (1) ◽  
pp. 135-142 ◽  
Author(s):  
Daisuke Oikawa ◽  
Yukio Kimata ◽  
Masato Takeuchi ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Recombinant Protein ◽  
Endoplasmic Reticulum Stress ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Recombinant Fragments ◽  
Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

scholarly journals Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1897 ◽  
Author(s):  
Alexander McQuiston ◽  
J Alan Diehl
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Transmembrane Protein ◽  
Downstream Signaling ◽  
Unfolded Protein ◽  
Evolutionarily Conserved ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an evolutionarily conserved stress response to intra- and extracellular conditions that disrupt endoplasmic reticulum (ER) protein-folding capacity. The UPR is engaged by a variety of disease conditions, including most cancers as well as both metabolic and neurodegenerative disorders. Three transmembrane transducers—PERK, IRE1, and ATF6—are responsible for activating downstream signaling pathways that mediate the UPR and subsequent stress response pathways. PERK, an ER resident transmembrane protein kinase, initiates both pro-apoptotic and pro-survival signaling pathways. In the context of neoplasia, PERK and its downstream targets alter gene expression that can be both pro- and anti-tumorigenic. In this review, we discuss recent advances in understanding how canonical and non-canonical PERK-mediated signaling pathways influence cell fate, tumor progression, and tumor suppression and avenues for therapeutic intervention.

scholarly journals Degradation of a Short-lived Glycoprotein from the Lumen of the Endoplasmic Reticulum: The Role of N-linked Glycans and the Unfolded Protein Response

1999 ◽  
Vol 10 (12) ◽  
pp. 4059-4073 ◽  
Author(s):  
Maddalena de Virgilio ◽  
Claudia Kitzmüller ◽  
Eva Schwaiger ◽  
Michael Klein ◽  
Gert Kreibich ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
The Other ◽  
Slow Phase ◽  
Type I ◽  
Unfolded Protein ◽  
Other Hand ◽  
The Unfolded Protein Response ◽  
Protein Response

We are studying endoplasmic reticulum–associated degradation (ERAD) with the use of a truncated variant of the type I ER transmembrane glycoprotein ribophorin I (RI). The mutant protein, RI332, containing only the N-terminal 332 amino acids of the luminal domain of RI, has been shown to interact with calnexin and to be a substrate for the ubiquitin-proteasome pathway. When RI332 was expressed in HeLa cells, it was degraded with biphasic kinetics; an initial, slow phase of ∼45 min was followed by a second phase of threefold accelerated degradation. On the other hand, the kinetics of degradation of a form of RI332 in which the single used N-glycosylation consensus site had been removed (RI332-Thr) was monophasic and rapid, implying a role of the N-linked glycan in the first proteolytic phase. RI332degradation was enhanced when the binding of glycoproteins to calnexin was prevented. Moreover, the truncated glycoprotein interacted with calnexin preferentially during the first proteolytic phase, which strongly suggests that binding of RI332 to the lectin-like protein may result in the slow, initial phase of degradation. Additionally, mannose trimming appears to be required for efficient proteolysis of RI332. After treatment of cells with the inhibitor of N-glycosylation, tunicamycin, destruction of the truncated RI variants was severely inhibited; likewise, in cells preincubated with the calcium ionophore A23187, both RI332 and RI332-Thr were stabilized, despite the presence or absence of the N-linked glycan. On the other hand, both drugs are known to trigger the unfolded protein response (UPR), resulting in the induction of BiP and other ER-resident proteins. Indeed, only in drug-treated cells could an interaction between BiP and RI332 and RI332-Thr be detected. Induction of BiP was also evident after overexpression of murine Ire1, an ER transmembrane kinase known to play a central role in the UPR pathway; at the same time, stabilization of RI332 was observed. Together, these results suggest that binding of the substrate proteins to UPR-induced chaperones affects their half lives.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

scholarly journals Endoplasmic reticulum stress and the development of endothelial dysfunction

2017 ◽  
Vol 312 (3) ◽  
pp. H355-H367 ◽  
Author(s):  
M. L. Battson ◽  
D. M. Lee ◽  
C. L. Gentile
Keyword(s):  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Critical Role ◽  
Unfolded Protein ◽  
Vasoactive Substances ◽  
Important Regulator ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.

scholarly journals Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1071 ◽  
Author(s):  
Yuxiang Fan ◽  
Thomas Simmen
Keyword(s):  
Endoplasmic Reticulum ◽  
Krebs Cycle ◽  
Membrane Dynamics ◽  
Mitochondrial Metabolism ◽  
Mitofusin 2 ◽  
Unfolded Protein ◽  
Transport Chain ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

The past decade has seen the emergence of endoplasmic reticulum (ER) chaperones as key determinants of contact formation between mitochondria and the ER on the mitochondria-associated membrane (MAM). Despite the known roles of ER–mitochondria tethering factors like PACS-2 and mitofusin-2, it is not yet entirely clear how they mechanistically interact with the ER environment to determine mitochondrial metabolism. In this article, we review the mechanisms used to communicate ER redox and folding conditions to the mitochondria, presumably with the goal of controlling mitochondrial metabolism at the Krebs cycle and at the electron transport chain, leading to oxidative phosphorylation (OXPHOS). To achieve this goal, redox nanodomains in the ER and the interorganellar cleft influence the activities of ER chaperones and Ca2+-handling proteins to signal to mitochondria. This mechanism, based on ER chaperones like calnexin and ER oxidoreductases like Ero1α, controls reactive oxygen production within the ER, which can chemically modify the proteins controlling ER–mitochondria tethering, or mitochondrial membrane dynamics. It can also lead to the expression of apoptotic or metabolic transcription factors. The link between mitochondrial metabolism and ER homeostasis is evident from the specific functions of mitochondria–ER contact site (MERC)-localized Ire1 and PERK. These functions allow these two transmembrane proteins to act as mitochondria-preserving guardians, a function that is apparently unrelated to their functions in the unfolded protein response (UPR). In scenarios where ER stress cannot be resolved via the activation of mitochondrial OXPHOS, MAM-localized autophagosome formation acts to remove defective portions of the ER. ER chaperones such as calnexin are again critical regulators of this MERC readout.

scholarly journals Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum

2016 ◽  
Vol 397 (7) ◽  
pp. 649-656 ◽  
Author(s):  
Alexander R. van Vliet ◽  
Abhishek D. Garg ◽  
Patrizia Agostinis
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathways ◽  
Unfolded Protein ◽  
Independent Functions ◽  
Intracellular Ca ◽  
Stress Signals ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

AbstractThe endoplasmic reticulum (ER) is the main coordinator of intracellular Ca2+signaling, protein synthesis, and folding. The ER is also implicated in the formation of contact sites with other organelles and structures, including mitochondria, plasma membrane (PM), and endosomes, thereby orchestrating through interorganelle signaling pathways, a variety of cellular responses including Ca2+homeostasis, metabolism, and cell death signaling. Upon loss of its folding capacity, incited by a number of stress signals including those elicited by various anticancer therapies, the unfolded protein response (UPR) is launched to restore ER homeostasis. The ER stress sensor protein kinase RNA-like ER kinase (PERK) is a key mediator of the UPR and its role during ER stress has been largely recognized. However, growing evidence suggests that PERK may govern signaling pathways through UPR-independent functions. Here, we discuss emerging noncanonical roles of PERK with particular relevance for the induction of danger or immunogenic signaling and interorganelle communication.

Endoplasmic reticulum stress in biological processing and disease

2021 ◽  
Vol 69 (2) ◽  
pp. 309-315
Author(s):  
Ali Riza Koksal ◽  
George Nicholas Verne ◽  
QiQi Zhou
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Chronic Diseases ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Inflammatory Bowel ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Multiple Signaling

The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases.

scholarly journals Adaptation to Endoplasmic Reticulum Stress Requires Transphosphorylation within the Activation Loop of Protein Kinases Kin1 and Kin2, Orthologs of Human Microtubule Affinity-Regulating Kinase

2018 ◽  
Vol 38 (23) ◽  
Author(s):  
Chandrima Ghosh ◽  
Leena Sathe ◽  
Joel David Paprocki ◽  
Valerica Raicu ◽  
Madhusudan Dey
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cellular Membrane ◽  
Kinase Domain ◽  
Activation Loop ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

ABSTRACT Perturbations in endoplasmic reticulum (ER) homeostasis, a condition termed ER stress, activate the unfolded protein response (UPR), an intracellular network of signaling pathways. Recently, we have shown that protein kinase Kin1 and its paralog, Kin2, in the budding yeast Saccharomyces cerevisiae (orthologs of microtubule affinity-regulating kinase in humans) contribute to the UPR function. These Kin kinases contain a conserved kinase domain and an autoinhibitory kinase-associated 1 (KA1) domain separated by a long undefined domain. Here, we show that Kin1 or Kin2 protein requires minimally a kinase domain and an adjacent kinase extension region (KER) for UPR function. We also show that the functional mini-Kin2 protein is predominantly visualized inside the cells and precipitated with the cellular membrane fraction, suggesting its association with the cellular endomembrane system. Furthermore, we show that transphosphorylation of the Kin1 residue T302 and the analogous Kin2 residue T281 within the activation loop are important for full kinase activity. Collectively, our data suggest that, during ER stress, the Kin kinase domain is released from its autoinhibitory KA1 domain and is activated by transphosphorylation.

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