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 RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

2014 ◽  
Vol 5 (12) ◽  
pp. e1555-e1555 ◽  
Author(s):  
Y Estornes ◽  
M A Aguileta ◽  
C Dubuisson ◽  
J De Keyser ◽  
V Goossens ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Life And Death ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

scholarly journals Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mable Lam ◽  
Scot A Marsters ◽  
Avi Ashkenazi ◽  
Peter Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Cell Fate ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Misfolded Proteins ◽  
Death Receptor 5 ◽  
Unfolded Protein ◽  
Late Protein ◽  
The Unfolded Protein Response

Disruption of protein folding in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)—a signaling network that ultimately determines cell fate. Initially, UPR signaling aims at cytoprotection and restoration of ER homeostasis; that failing, it drives apoptotic cell death. ER stress initiates apoptosis through intracellular activation of death receptor 5 (DR5) independent of its canonical extracellular ligand Apo2L/TRAIL; however, the mechanism underlying DR5 activation is unknown. In cultured human cells, we find that misfolded proteins can directly engage with DR5 in the ER-Golgi intermediate compartment, where DR5 assembles pro-apoptotic caspase 8-activating complexes. Moreover, peptides used as a proxy for exposed misfolded protein chains selectively bind to the purified DR5 ectodomain and induce its oligomerization. These findings indicate that misfolded proteins can act as ligands to activate DR5 intracellularly and promote apoptosis. We propose that cells can use DR5 as a late protein-folding checkpoint before committing to a terminal apoptotic fate.

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.

Endoplasmic Reticulum Stress: Signaling the Unfolded Protein Response

Physiology ◽  
2007 ◽  
Vol 22 (3) ◽  
pp. 193-201 ◽  
Author(s):  
Elida Lai ◽  
Tracy Teodoro ◽  
Allen Volchuk
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Apoptotic Cell ◽  
Signaling Cascades ◽  
Stress Signaling ◽  
Apoptosis Induction ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the cellular site of newly synthesized secretory and membrane proteins. Such proteins must be properly folded and posttranslationally modified before exit from the organelle. Proper protein folding and modification requires molecular chaperone proteins as well as an ER environment conducive for these reactions. When ER lumenal conditions are altered or chaperone capacity is overwhelmed, the cell activates signaling cascades that attempt to deal with the altered conditions and restore a favorable folding environment. Such alterations are referred to as ER stress, and the response activated is the unfolded protein response (UPR). When the UPR is perturbed or not sufficient to deal with the stress conditions, apoptotic cell death is initiated. This review will examine UPR signaling that results in cell protective responses, as well as the mechanisms leading to apoptosis induction, which can lead to pathological states due to chronic ER stress.

scholarly journals Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate

2018 ◽  
Vol 71 (4) ◽  
pp. 629-636.e5 ◽  
Author(s):  
Tsun-Kai Chang ◽  
David A. Lawrence ◽  
Min Lu ◽  
Jenille Tan ◽  
Jonathan M. Harnoss ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Apoptotic Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

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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