scholarly journals Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α

2002 ◽  
Vol 22 (24) ◽  
pp. 8506-8513 ◽  
Author(s):  
Monica G. Marcu ◽  
Melissa Doyle ◽  
Anne Bertolotti ◽  
David Ron ◽  
Linda Hendershot ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Specific Inhibitor ◽  
Transcriptional Response ◽  
Heat Shock Protein 90 ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
And Function ◽  
Protein Response

ABSTRACT The molecular chaperone HSP90 regulates stability and function of multiple protein kinases. The HSP90-binding drug geldanamycin interferes with this activity and promotes proteasome-dependent degradation of most HSP90 client proteins. Geldanamycin also binds to GRP94, the HSP90 paralog located in the endoplasmic reticulum (ER). Because two of three ER stress sensors are transmembrane kinases, namely IRE1α and PERK, we investigated whether HSP90 is necessary for the stability and function of these proteins. We found that HSP90 associates with the cytoplasmic domains of both kinases. Both geldanamycin and the HSP90-specific inhibitor, 514, led to the dissociation of HSP90 from the kinases and a concomitant turnover of newly synthesized and existing pools of these proteins, demonstrating that the continued association of HSP90 with the kinases was required to maintain their stability. Further, the previously reported ability of geldanamycin to stimulate ER stress-dependent transcription apparently depends on its interaction with GRP94, not HSP90, since geldanamycin but not 514 led to up-regulation of BiP. However, this effect is eventually superseded by HSP90-dependent destabilization of unfolded protein response signaling. These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade.

scholarly journals Hypoxia-induced SETX links replication stress with the unfolded protein response

2020 ◽  
Author(s):  
Shaliny Ramachandran ◽  
Tiffany Ma ◽  
Natalie Ng ◽  
Iosifina P. Foskolou ◽  
Ming-Shih Hwang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Unfolded Protein Response ◽  
Cellular Response ◽  
Biological Response ◽  
Transcriptional Response ◽  
Replication Stress ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

ABSTRACTThe levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, we show that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological hypoxia, which includes both a replication stress dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

scholarly journals Regulation of the Unfolded Protein Response by BiP AMPylation protects photoreceptors from light-dependent degeneration

2018 ◽  
Author(s):  
Andrew T. Moehlman ◽  
Amanda K. Casey ◽  
Kelly Servage ◽  
Kim Orth ◽  
Helmut Krämer
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Synaptic Function ◽  
Transient Stress ◽  
Unfolded Protein ◽  
Response To Stress ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Light:Dark Cycle

AbstractIn response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, the Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress. After 72 hours of constant light, photoreceptors of fic-null and AMPylation-resistant BiPT366A mutants, but not wild-type flies, display loss of synaptic function, disintegration of rhabdomeres, and excessive activation of ER stress reporters. Strikingly, this phenotype is reversible: photoreceptors regain their structure and function within 72 hours once returned to a standard light:dark cycle. These findings show that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands.

scholarly journals The unfolded protein response in Pichia pastoris without external stressing stimuli

2020 ◽  
Vol 20 (7) ◽  
Author(s):  
Yasmin Nabilah Binti Mohd Fauzee ◽  
Naoki Taniguchi ◽  
Yuki Ishiwata-Kimata ◽  
Hiroshi Takagi ◽  
Yukio Kimata
Keyword(s):  
Pichia Pastoris ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Gene Knockout ◽  
Transmembrane Protein ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

ABSTRACT Dysfunction or capacity shortage of the endoplasmic reticulum (ER) is cumulatively called ER stress and provokes the unfolded protein response (UPR). In various yeast species, the ER-located transmembrane protein Ire1 is activated upon ER stress and performs the splicing reaction of HAC1 mRNA, the mature form of which is translated into a transcription factor protein that is responsible for the transcriptome change on the UPR. Here we carefully assessed the splicing of HAC1 mRNA in Pichia pastoris (Komagataella phaffii) cells. We found that, inconsistent with previous reports by others, the HAC1 mRNA was substantially, but partially, spliced even without ER-stressing stimuli. Unlike Saccharomyces cerevisiae, growth of P. pastoris was significantly retarded by the IRE1-gene knockout mutation. Moreover, P. pastoris cells seemed to push more abundant proteins into the secretory pathway than S. cerevisiae cells. We also suggest that P. pastoris Ire1 has the ability to control its activity stringently in an ER stress-dependent manner. We thus propose that P. pastoris cells are highly ER-stressed possibly because of the high load of endogenous proteins into the ER.

Inhibition of the PI 3‐kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress‐dependent apoptosis

2020 ◽  
Vol 34 (9) ◽  
pp. 12521-12532
Author(s):  
Jonathon N. Winnay ◽  
Marie H. Solheim ◽  
Masaji Sakaguchi ◽  
Pål R. Njølstad ◽  
C. Ronald Kahn
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
Kinase Pathway

scholarly journals Adaptation to constant light requires Fic-mediated AMPylation of BiP to protect against reversible photoreceptor degeneration

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Andrew T Moehlman ◽  
Amanda K Casey ◽  
Kelly Servage ◽  
Kim Orth ◽  
Helmut Krämer
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Synaptic Function ◽  
Constant Light ◽  
Unfolded Protein ◽  
Response To Stress ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Light:Dark Cycle

In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, the Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress. After 72 hr of constant light, photoreceptors of fic-null and AMPylation-resistant BiPT366A mutants, but not wild-type flies, display loss of synaptic function, disintegration of rhabdomeres, and excessive activation of ER stress reporters. Strikingly, this phenotype is reversible: photoreceptors regain their structure and function within 72 hr once returned to a standard light:dark cycle. These findings show that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands.

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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