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.

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 Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria–ER Contacts: A Cancer Perspective

2021 ◽  
Vol 9 ◽  
Author(s):  
Giuseppina Amodio ◽  
Valentina Pagliara ◽  
Ornella Moltedo ◽  
Paolo Remondelli
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Tumor Development ◽  
Unfolded Protein ◽  
Mitochondria Dynamics ◽  
Fate Decision ◽  
The Unfolded Protein Response ◽  
Almost All ◽  
Protein Response

In the last decades, the endoplasmic reticulum (ER) has emerged as a key coordinator of cellular homeostasis, thanks to its physical interconnection to almost all intracellular organelles. In particular, an intense and mutual crosstalk between the ER and mitochondria occurs at the mitochondria–ER contacts (MERCs). MERCs ensure a fine-tuned regulation of fundamental cellular processes, involving cell fate decision, mitochondria dynamics, metabolism, and proteostasis, which plays a pivotal role in the tumorigenesis and therapeutic response of cancer cells. Intriguingly, recent studies have shown that different components of the unfolded protein response (UPR) machinery, including PERK, IRE1α, and ER chaperones, localize at MERCs. These proteins appear to exhibit multifaceted roles that expand beyond protein folding and UPR transduction and are often related to the control of calcium fluxes to the mitochondria, thus acquiring relevance to cell survival and death. In this review, we highlight the novel functions played by PERK, IRE1α, and ER chaperones at MERCs focusing on their impact on tumor development.

scholarly journals Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

2019 ◽  
Vol 71 (5) ◽  
pp. 1659-1667 ◽  
Author(s):  
Taiaba Afrin ◽  
Danish Diwan ◽  
Katrina Sahawneh ◽  
Karolina Pajerowska-Mukhtar
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Translational Control ◽  
Protein Quality ◽  
Unfolded Protein ◽  
Transcriptional Gene Regulation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

BLIMP-1 Is a Target of Cellular Stress and Downstream of the Unfolded Protein Response.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2207-2207
Author(s):  
Gina Doody ◽  
Sophie Stephenson ◽  
Reuben Tooze
Keyword(s):  
Cell Differentiation ◽  
Stress Response ◽  
Virus Infection ◽  
B Cell ◽  
Signaling Pathways ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Eif2α Kinase ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Human B lymphocyte-induced maturation protein-1 (BLIMP-1) was originally described as a repressor of the interferon-beta response to viral infection. Subsequently, the murine orthologue was identified as a regulator of plasma cell differentiation. The involvement of BLIMP-1 in hemopoietic differentiation is not restricted to the B-cell lineage as BLIMP-1 is induced during differentiation of myeloid progenitors. During in vitro macrophage and plasma cell differentiation the expression of BLIMP-1 is cytokine driven. However, the BLIMP-1 response to virus infection can be reproduced by transfection with double-stranded RNA (dsRNA), indicating that BLIMP-1 is a target of dsRNA responsive signaling pathways. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated kinase, PKR. PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2α) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum (ER) PKR-homologue is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested the hypothesis that BLIMP-1 may represent a shared target of signaling pathways in the response to cellular stresses such as virus infection and the UPR. In this study we demonstrate that BLIMP-1 is rapidly upregulated during the UPR in human myeloid and B-cell lines. This response is conserved in primary murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription, with enhanced recruitment of RNA polymerase II to the BLIMP-1 promoter. Furthermore the stress response is limited to induction of BLIMP-1α mRNA and does not affect levels of an alternate transcript encoding a truncated protein, BLIMP-1β. The common induction of BLIMP-1 mRNA by stimuli which trigger the UPR supports the hypothesis that BLIMP-1 is a target of the eIF2α kinase family. To test this hypothesis directly, we employed a dominant negative mutant PERK. Our data demonstrate that the BLIMP-1 response to UPR stress is dependent on an intact PERK signaling pathway. Collectively our results provide evidence for a novel link between cellular stress, the eIF2α kinase family and a regulator of differentiation in macrophages and B-cells.

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.

scholarly journals The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

2019 ◽  
Author(s):  
Rebecca A.S. Palu ◽  
Clement Y. Chow
Keyword(s):  
Endoplasmic Reticulum ◽  
Drosophila Melanogaster ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Membrane Bound ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACTEndoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster, which we rename as SUPpressor of ER stress-induced DEATH (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the Rh1G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans. Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways.SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients. One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.

scholarly journals The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

2021 ◽  
Author(s):  
Kashi Raj Bhattarai ◽  
Thoufiqul Alam Riaz ◽  
Hyung-Ryong Kim ◽  
Han-Jung Chae
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Stress Response ◽  
Er Stress ◽  
Protein Modification ◽  
Endoplasmic Reticulum Stress Response ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

scholarly journals Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation

2006 ◽  
Vol 172 (3) ◽  
pp. 383-393 ◽  
Author(s):  
Yukako Oda ◽  
Tetsuya Okada ◽  
Hiderou Yoshida ◽  
Randal J. Kaufman ◽  
Kazuhiro Nagata ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Missing Link ◽  
Unfolded Protein ◽  
Accelerated Degradation ◽  
The Unfolded Protein Response ◽  
Protein Response

Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. Components of both productive folding and ER-associated degradation (ERAD) mechanisms are known to be up-regulated by the unfolded protein response (UPR). We describe two novel components of mammalian ERAD, Derlin-2 and -3, which show weak homology to Der1p, a transmembrane protein involved in yeast ERAD. Both Derlin-2 and -3 are up-regulated by the UPR, and at least Derlin-2 is a target of the IRE1 branch of the response, which is known to up-regulate ER degradation enhancing α-mannosidase–like protein (EDEM) and EDEM2, receptor-like molecules for misfolded glycoprotein. Overexpression of Derlin-2 or -3 accelerated degradation of misfolded glycoprotein, whereas their knockdown blocked degradation. Derlin-2 and -3 are associated with EDEM and p97, a cytosolic ATPase responsible for extraction of ERAD substrates. These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins.

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