The unfolded protein response: controlling cell fate decisions under ER stress and beyond

2012 ◽  
Vol 13 (2) ◽  
pp. 89-102 ◽  
Author(s):  
Claudio Hetz
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

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 Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress

Redox Biology ◽  
2019 ◽  
Vol 25 ◽  
pp. 101047 ◽  
Author(s):  
Zhe Zhang ◽  
Lu Zhang ◽  
Li Zhou ◽  
Yunlong Lei ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Redox Signaling ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
Protein Response

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 The Unfolded Protein Response and Membrane Contact Sites: Tethering as a Matter of Life and Death?

Contact ◽  
2018 ◽  
Vol 1 ◽  
pp. 251525641877051 ◽  
Author(s):  
Alexander R. van Vliet ◽  
Maria Livia Sassano ◽  
Patrizia Agostinis
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the most extensive organelle of the eukaryotic cell and constitutes the major site of protein and lipid synthesis and regulation of intracellular Ca2+ levels. To exert these functions properly, the ER network is shaped in structurally and functionally distinct domains that dynamically remodel in response to intrinsic and extrinsic cues. Moreover, the ER establishes a tight communication with virtually all organelles of the cell through specific subdomains called membrane contact sites. These contact sites allow preferential, nonvesicular channeling of key biological mediators including lipids and Ca2+ between organelles and are harnessed by the ER to interface with and coregulate a variety of organellar functions that are vital to maintain homeostasis. When ER homeostasis is lost, a condition that triggers the activation of an evolutionarily conserved pathway called the unfolded protein response (UPR), the ER undergoes rapid remodeling. These dynamic changes in ER morphology are functionally coupled to the modulation or formation of contact sites with key organelles, such as mitochondria and the plasma membrane, which critically regulate cell fate decisions of the ER-stressed cells. Certain components of the UPR have been shown to facilitate the formation of contact sites through various mechanisms including remodeling of the actin cytoskeleton. In this review, we discuss old and emerging evidence linking the UPR machinery to contact site formation in mammalian cells and discuss their important role in cellular homeostasis.

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.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

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