scholarly journals The UPRosome – decoding novel biological outputs of IRE1α function

2020 ◽  
Vol 133 (15) ◽  
pp. jcs218107 ◽  
Author(s):  
Hery Urra ◽  
Philippe Pihán ◽  
Claudio Hetz
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
Biological Significance ◽  
Functional Enrichment ◽  
Data Sets ◽  
Unfolded Protein ◽  
Binding Partners ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cytoskeleton Dynamics

ABSTRACTDifferent perturbations alter the function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins in its lumen, a condition termed ER stress. To restore ER proteostasis, a highly conserved pathway is engaged, known as the unfolded protein response (UPR), triggering adaptive programs or apoptosis of terminally damaged cells. IRE1α (also known as ERN1), the most conserved UPR sensor, mediates the activation of responses to determine cell fate under ER stress. The complexity of IRE1α regulation and its signaling outputs is mediated in part by the assembly of a dynamic multi-protein complex, named the UPRosome, that regulates IRE1α activity and the crosstalk with other pathways. We discuss several studies identifying components of the UPRosome that have illuminated novel functions in cell death, autophagy, DNA damage, energy metabolism and cytoskeleton dynamics. Here, we provide a theoretical analysis to assess the biological significance of the UPRosome and present the results of a systematic bioinformatics analysis of the available IRE1α interactome data sets followed by functional enrichment clustering. This in silico approach decoded that IRE1α also interacts with proteins involved in the cell cycle, transport, differentiation, response to viral infection and immune response. Thus, defining the spectrum of IRE1α-binding partners will reveal novel signaling outputs and the relevance of the pathway to human diseases.

scholarly journals Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis

Science ◽  
2014 ◽  
Vol 345 (6192) ◽  
pp. 98-101 ◽  
Author(s):  
Min Lu ◽  
David A. Lawrence ◽  
Scot Marsters ◽  
Diego Acosta-Alvear ◽  
Philipp Kimmig ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Receptor 5 ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

scholarly journals The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 156
Author(s):  
Natalia Siwecka ◽  
Wioletta Rozpędek-Kamińska ◽  
Adam Wawrzynkiewicz ◽  
Dariusz Pytel ◽  
J. Alan Diehl ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
Stress Conditions ◽  
Molecular Characteristics ◽  
Detailed Knowledge ◽  
Drug Candidates ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
The Unfolded Protein Response ◽  
Protein Response

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.

scholarly journals The Sec61 translocon limits IRE1α signaling during the unfolded protein response

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Arunkumar Sundaram ◽  
Rachel Plumb ◽  
Suhila Appathurai ◽  
Malaiyalam Mariappan
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
Stress Conditions ◽  
Native Page ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
Blue Native Page ◽  
Oligomeric Complex ◽  
The Unfolded Protein Response ◽  
Protein Response

IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (<xref ref-type="bibr" rid="bib39">Plumb et al., 2015</xref>). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1α oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1α-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1α to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1α complex defines the extent of IRE1α activity and may determine cell fate decisions during ER stress conditions.

scholarly journals Small molecule strategies to harness the unfolded protein response: where do we go from here?

2020 ◽  
Vol 295 (46) ◽  
pp. 15692-15711 ◽  
Author(s):  
Julia M. D. Grandjean ◽  
R. Luke Wiseman
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Human Disease ◽  
Lessons Learned ◽  
Cellular Physiology ◽  
Unfolded Protein ◽  
Advantages And Disadvantages ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) plays a central role in regulating endoplasmic reticulum (ER) and global cellular physiology in response to pathologic ER stress. The UPR is comprised of three signaling pathways activated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Once activated, these proteins initiate transcriptional and translational signaling that functions to alleviate ER stress, adapt cellular physiology, and dictate cell fate. Imbalances in UPR signaling are implicated in the pathogenesis of numerous, etiologically-diverse diseases, including many neurodegenerative diseases, protein misfolding diseases, diabetes, ischemic disorders, and cancer. This has led to significant interest in establishing pharmacologic strategies to selectively modulate IRE1, ATF6, or PERK signaling to both ameliorate pathologic imbalances in UPR signaling implicated in these different diseases and define the importance of the UPR in diverse cellular and organismal contexts. Recently, there has been significant progress in the identification and characterization of UPR modulating compounds, providing new opportunities to probe the pathologic and potentially therapeutic implications of UPR signaling in human disease. Here, we describe currently available UPR modulating compounds, specifically highlighting the strategies used for their discovery and specific advantages and disadvantages in their application for probing UPR function. Furthermore, we discuss lessons learned from the application of these compounds in cellular and in vivo models to identify favorable compound properties that can help drive the further translational development of selective UPR modulators for human disease.

scholarly journals BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress

2019 ◽  
Vol 218 (9) ◽  
pp. 3002-3018 ◽  
Author(s):  
Fei-Yun Chen ◽  
Min-Yu Huang ◽  
Yu-Min Lin ◽  
Chi-Huan Ho ◽  
Shu-Yu Lin ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Unfolded Protein ◽  
Ubiquitin Proteasome ◽  
Cellular Stresses ◽  
The Unfolded Protein Response ◽  
Protein Response

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin–proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α–XBP1s–ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

scholarly journals QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis

Science ◽  
2020 ◽  
Vol 371 (6524) ◽  
pp. eabb6896
Author(s):  
Kwontae You ◽  
Lingfei Wang ◽  
Chih-Hung Chou ◽  
Kai Liu ◽  
Toru Nakata ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Cell Fate ◽  
Protein Misfolding ◽  
Transcriptional Control ◽  
Stress Protein ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Genome Scale

Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.

scholarly journals Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

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