scholarly journals Intermolecular disulfide-bond formation in human FICD modulates the activity of the hyperactive E234G mutant

2017 ◽  
Author(s):  
Raffaella Magnoni ◽  
Minttu S. Virolainen ◽  
Celeste M. Hackney ◽  
Cecilie L. Søltoft ◽  
Ana P. Cordeiro ◽  
...  
Keyword(s):  
Protein Folding ◽  
Er Stress ◽  
Redox Homeostasis ◽  
Functional Connection ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Intermolecular Disulfide Bond ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Homeostatic Response

AbstractEndoplasmic reticulum (ER) stress that leads to the accumulation of misfolded proteins in the ER initiates the unfolded protein response (UPR). This homeostatic response activates signaling pathways that seek to reinstate a proper ER protein folding balance or induce apoptosis if ER stress persists. Recently, we and others identified human FICD (Filamentation induced by cyclic AMP domain-containing protein), an enzyme with adenylyltransferase (aka AMPylation) activity, as a new UPR target. Here, we demonstrate that FICD is functionally linked to the UPR, as evidenced by the finding that the adenylyltransferase activity of the protein induces ER stress, while FICD silencing increases sensitivity to ER stress. We identify BiP, an abundant ER chaperone and key regulator of the UPR, as the main substrate of FICD AMPylation in ER-derived microsomes, further emphasizing close functional connection of FICD to the UPR and in line with recent reports that AMPylation inactivates BiP. Notably, BiP overexpression increased the levels of BiP AMPylation as well as FICD auto-AMPylation, suggesting a homeostatic response that balances the pool of active BiP to modulate its functions in protein folding as well as UPR signaling. Finally, we show that overexpressed FICD forms a disulfide-bonded homo-dimer through Cys51 and Cys75 and demonstrate that mutation of these two cysteines in the context of a hyperactive FICD mutant leads to increased BiP AMPylation. This latter finding opens up the possibility that FICD activity is redox regulated and closely connected with ER redox homeostasis.

scholarly journals The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Philipp Kimmig ◽  
Marcy Diaz ◽  
Jiashun Zheng ◽  
Christopher C Williams ◽  
Alexander Lang ◽  
...  
Keyword(s):  
Er Stress ◽  
Fission Yeast ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Stress Sensing ◽  
Transcription Activators ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Selective Decay

The unfolded protein response (UPR) monitors the protein folding capacity of the endoplasmic reticulum (ER). In all organisms analyzed to date, the UPR drives transcriptional programs that allow cells to cope with ER stress. The non-conventional splicing of Hac1 (yeasts) and XBP1 (metazoans) mRNA, encoding orthologous UPR transcription activators, is conserved and dependent on Ire1, an ER membrane-resident kinase/endoribonuclease. We found that the fission yeast Schizosaccharomyces pombe lacks both a Hac1/XBP1 ortholog and a UPR-dependent-transcriptional-program. Instead, Ire1 initiates the selective decay of a subset of ER-localized-mRNAs that is required to survive ER stress. We identified Bip1 mRNA, encoding a major ER-chaperone, as the sole mRNA cleaved upon Ire1 activation that escapes decay. Instead, truncation of its 3′ UTR, including loss of its polyA tail, stabilized Bip1 mRNA, resulting in increased Bip1 translation. Thus, S. pombe uses a universally conserved stress-sensing machinery in novel ways to maintain homeostasis in the ER.

scholarly journals Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Anush Bakunts ◽  
Andrea Orsi ◽  
Milena Vitale ◽  
Angela Cattaneo ◽  
Federica Lari ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Heavy Chain ◽  
Immunoglobulin M ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Ideal System ◽  
The Unfolded Protein Response ◽  
Protein Response

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, as in most studies the ER stress that is elicited cannot be overcome. Here we show that a proteostatic insult, provoked by persistent expression of the secretory heavy chain of immunoglobulin M (µs), is well-tolerated in HeLa cells. Upon µs expression, its levels temporarily eclipse those of the ER chaperone BiP, leading to acute, full-geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER stress in a ratiometric fashion. In this process, the ER expands about three-fold and becomes dominated by BiP. As the UPR is essential for successful ER homeostatic readjustment in the HeLa-µs model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER stress.

scholarly journals Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response

2009 ◽  
Vol 187 (4) ◽  
pp. 525-536 ◽  
Author(s):  
Sebastian Schuck ◽  
William A. Prinz ◽  
Kurt S. Thorn ◽  
Christiane Voss ◽  
Peter Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Size Control ◽  
Yeast Saccharomyces Cerevisiae ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Key Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

Cells constantly adjust the sizes and shapes of their organelles according to need. In this study, we examine endoplasmic reticulum (ER) membrane expansion during the unfolded protein response (UPR) in the yeast Saccharomyces cerevisiae. We find that membrane expansion occurs through the generation of ER sheets, requires UPR signaling, and is driven by lipid biosynthesis. Uncoupling ER size control and the UPR reveals that membrane expansion alleviates ER stress independently of an increase in ER chaperone levels. Converting the sheets of the expanded ER into tubules by reticulon overexpression does not affect the ability of cells to cope with ER stress, showing that ER size rather than shape is the key factor. Thus, increasing ER size through membrane synthesis is an integral yet distinct part of the cellular program to overcome ER stress.

scholarly journals The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

2021 ◽  
Author(s):  
Kashi Raj Bhattarai ◽  
Thoufiqul Alam Riaz ◽  
Hyung-Ryong Kim ◽  
Han-Jung Chae
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Stress Response ◽  
Er Stress ◽  
Protein Modification ◽  
Endoplasmic Reticulum Stress Response ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

Activation of the Unfolded Protein Response (UPR) Induces CEBPA mRNA Decay in AML Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2258-2258
Author(s):  
Marianne Eyholzer ◽  
Julian Schardt ◽  
Deborah Shan ◽  
Beatrice U Mueller ◽  
Thomas Pabst
Keyword(s):  
Protein Folding ◽  
Er Stress ◽  
Mrna Expression ◽  
Unfolded Protein Response ◽  
Mrna Decay ◽  
Leukemic Cells ◽  
Hl60 Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The myeloid key transcription factor CEBPA (CCAAT-enhancer binding protein alpha) is crucial for normal neutrophil differentiation, and cebpa-deficient mice lack mature granulocytes. In addition, deregulation of CEBPA function is a frequent event in AML patients. The endoplasmatic reticulum (ER) is involved in proper protein folding. Alterations in calcium levels or insufficient protein folding capacity leads to ER stress, thereby inducing rescue pathways that are commonly summarized as the unfolded protein response (UPR). The UPR aims either to re-establish ER homeostasis or to induce cell death. So far, induction of ER stress has been associated with a number of non-hematopoietic diseases. Here, we analyzed whether activated ER stress in leukemic cell lines and in AML patients affects the myeloid key regulator CEBPA. We induced ER stress in the leukemic HL60 cell line by treatment with 0.4mg/ml of Calcimycin (deregulation of calcium homeostasis) or with 3mg/ml of Tunicamycin (block of protein glycosylation). Consistently, we observed a rapid decrease of CEBPA mRNA to 10% after 6 hours of treatment. In accordance, CEBPA protein was no more detectable after 8 hours. Experiments in HL60 cells with Actinomycin D and Cycloheximide as well as competition experiments with various constructs of wild-type CEBPA sequences suggest a decay mechanism involving one or several elements in the 3’UTR of the CEBPA mRNA. We excluded microRNA-124a, a previously identified CEBPA regulator acting through the 3’UTR, to be involved. The precise elements mediating ER stress induced CEBPA mRNA decay remain to be elucidated. We also determined the expression of CEBPA mRNA and mediators of UPR - such as CHOP and GRP78 as well as alternative splicing of the XBP1 mRNA - in leukemic cells from 76 AML patients of all FAB subtypes. We found that AML patients with induced ER stress (13%) tended to have two-fold lower CEBPA mRNA expression, thus underlining the in vitro results reported above. In conclusion, our experiments indicate activated ER stress to be involved in a significant subgroup of AML patients. Moreover, it suggests that activation of the UPR in myeloid leukemic cells efficiently induces 3’UTR mediated decay of CEBPA mRNA expression, thereby contributing to the block in myeloid differentiation in these leukemias.

scholarly journals Endoplasmic Reticulum Stress and Unfolded Protein Response Signaling in Plants

2022 ◽  
Vol 23 (2) ◽  
pp. 828
Author(s):  
Hakim Manghwar ◽  
Jianming Li
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Defense Mechanisms ◽  
Protein Complexes ◽  
Unfolded Protein ◽  
Subcellular Organelle ◽  
The Unfolded Protein Response ◽  
Protein Response

Plants are sensitive to a variety of stresses that cause various diseases throughout their life cycle. However, they have the ability to cope with these stresses using different defense mechanisms. The endoplasmic reticulum (ER) is an important subcellular organelle, primarily recognized as a checkpoint for protein folding. It plays an essential role in ensuring the proper folding and maturation of newly secreted and transmembrane proteins. Different processes are activated when around one-third of newly synthesized proteins enter the ER in the eukaryote cells, such as glycosylation, folding, and/or the assembling of these proteins into protein complexes. However, protein folding in the ER is an error-prone process whereby various stresses easily interfere, leading to the accumulation of unfolded/misfolded proteins and causing ER stress. The unfolded protein response (UPR) is a process that involves sensing ER stress. Many strategies have been developed to reduce ER stress, such as UPR, ER-associated degradation (ERAD), and autophagy. Here, we discuss the ER, ER stress, UPR signaling and various strategies for reducing ER stress in plants. In addition, the UPR signaling in plant development and different stresses have been discussed.

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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