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 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 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 MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response

2012 ◽  
Vol 196 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Andrew E. Byrd ◽  
Ileana V. Aragon ◽  
Joseph W. Brewer
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Translational Control ◽  
Secretory Pathway ◽  
Signaling System ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Secretory Capacity

Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a multifaceted signaling system coordinating translational control and gene transcription to promote cellular adaptation and survival. Microribonucleic acids (RNAs; miRNAs), single-stranded RNAs that typically function as posttranscriptional modulators of gene activity, have been shown to inhibit translation of certain secretory pathway proteins during the UPR. However, it remains unclear whether miRNAs regulate UPR signaling effectors directly. In this paper, we report that a star strand miRNA, miR-30c-2* (recently designated miR-30c-2-3p), is induced by the protein kinase RNA activated–like ER kinase (PERK) pathway of the UPR and governs expression of XBP1 (X-box binding protein 1), a key transcription factor that augments secretory capacity and promotes cell survival in the adaptive UPR. These data provide the first link between an miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PERK pathway, via miR-30c-2*, influences the scale of XBP1-mediated gene expression and cell fate in the UPR.

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.

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