Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Charcot Marie Tooth diseases type 1A (CMT1A), caused by duplication of Peripheral Myelin Protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene are the two most common forms of demyelinating CMT (CMT1) and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modeled by MpzR98C/+ mice that also show ER-stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER-stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER-stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analyzed by behavioral, neurophysiological, morphological and biochemical measures. Both MpzR98C/+ and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild type values. Taken together our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in Amyotrophic Lateral Sclerosis and Multiple Sclerosis animal models, these data demonstrate its potential in managing UPR and ER-stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases.

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ER stress and the unfolded protein response in intestinal inflammation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00063.2010 ◽

2010 ◽

Vol 298 (6) ◽

pp. G820-G832 ◽

Cited By ~ 107

Author(s):

Michael A. McGuckin ◽

Rajaraman D. Eri ◽

Indrajit Das ◽

Rohan Lourie ◽

Timothy H. Florin

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Intestinal Inflammation ◽

Secretory Cells ◽

Unfolded Protein ◽

Bowel Diseases ◽

Stressed Cells ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress is a phenomenon that occurs when excessive protein misfolding occurs during biosynthesis. ER stress triggers a series of signaling and transcriptional events known as the unfolded protein response (UPR). The UPR attempts to restore homeostasis in the ER but if unsuccessful can trigger apoptosis in the stressed cells and local inflammation. Intestinal secretory cells are susceptible to ER stress because they produce large amounts of complex proteins for secretion, most of which are involved in mucosal defense. This review focuses on ER stress in intestinal secretory cells and describes how increased protein misfolding could occur in these cells, the process of degradation of misfolded proteins, the major molecular elements of the UPR pathway, and links between the UPR and inflammation. Evidence is reviewed from mouse models and human inflammatory bowel diseases that ties ER stress and activation of the UPR with intestinal inflammation, and possible therapeutic approaches to ameliorate ER stress are discussed.

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Probiotics Supplements Reduce ER Stress and Gut Inflammation Associated with Gliadin Intake in a Mouse Model of Gluten Sensitivity

Nutrients ◽

10.3390/nu13041221 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1221

Author(s):

Eleonora Ferrari ◽

Romina Monzani ◽

Valentina Saverio ◽

Mara Gagliardi ◽

Elżbieta Pańczyszyn ◽

...

Keyword(s):

Mouse Model ◽

Er Stress ◽

Human Leukocyte ◽

Gut Inflammation ◽

Leukocyte Antigen ◽

Unfolded Protein ◽

Worldwide Population ◽

The Unfolded Protein Response ◽

Protein Response

Exposure to gluten, a protein present in wheat rye and barley, is the major inducer for human Celiac Disease (CD), a chronic autoimmune enteropathy. CD occurs in about 1% worldwide population, in genetically predisposed individuals bearing human leukocyte antigen (HLA) DQ2/DQ8. Gut epithelial cell stress and the innate immune activation are responsible for the breaking oral tolerance to gliadin, a gluten component. To date, the only treatment available for CD is a long-term gluten-free diet. Several studies have shown that an altered composition of the intestinal microbiota (dysbiosis) could play a key role in the pathogenesis of CD through the modulation of intestinal permeability and the regulation of the immune system. Here, we show that gliadin induces a chronic endoplasmic reticulum (ER) stress condition in the small intestine of a gluten-sensitive mouse model and that the coadministration of probiotics efficiently attenuates both the unfolded protein response (UPR) and gut inflammation. Moreover, the composition of probiotics formulations might differ in their activity at molecular level, especially toward the three axes of the UPR. Therefore, probiotics administration might potentially represent a new valuable strategy to treat gluten-sensitive patients, such as those affected by CD.

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Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response

Molecular Biology of the Cell ◽

10.1091/mbc.e13-11-0664 ◽

2014 ◽

Vol 25 (9) ◽

pp. 1411-1420 ◽

Cited By ~ 65

Author(s):

Nobuhiko Hiramatsu ◽

Carissa Messah ◽

Jaeseok Han ◽

Matthew M. LaVail ◽

Randal J. Kaufman ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Down Regulation ◽

Unfolded Protein ◽

Activity Loss ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

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The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote resistance to endoplasmic reticulum stress

10.1101/457077 ◽

2018 ◽

Author(s):

Rolf M. Schmidt ◽

Sebastian Schuck

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Misfolded Proteins ◽

Secretory Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Multiple Signaling

ABSTRACTMisfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.

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The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote ER stress resistance

eLife ◽

10.7554/elife.43244 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 13

Author(s):

Rolf M Schmidt ◽

Julia P Schessner ◽

Georg HH Borner ◽

Sebastian Schuck

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Stress Resistance ◽

Protein Misfolding ◽

Misfolded Proteins ◽

Secretory Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Multiple Signaling

Misfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.

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Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane

Blood ◽

10.1182/blood-2010-10-311704 ◽

2011 ◽

Vol 117 (13) ◽

pp. 3539-3547 ◽

Cited By ~ 45

Author(s):

Suparna Nanua ◽

Mark Murakami ◽

Jun Xia ◽

David S. Grenda ◽

Jill Woloszynek ◽

...

Keyword(s):

Transgenic Mice ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Strong Support ◽

Chemical Induction ◽

Granulocytic Differentiation ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Abstract Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis that in many cases is caused by mutations of the ELANE gene, which encodes neutrophil elastase (NE). Recent data suggest a model in which ELANE mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately a block in granulocytic differentiation. To test this model, we generated transgenic mice carrying a targeted mutation of Elane (G193X) reproducing a mutation found in SCN. The G193X Elane allele produces a truncated NE protein that is rapidly degraded. Granulocytic precursors from G193X Elane mice, though without significant basal UPR activation, are sensitive to chemical induction of ER stress. Basal and stress granulopoiesis after myeloablative therapy are normal in these mice. Moreover, inaction of protein kinase RNA-like ER kinase (Perk), one of the major sensors of ER stress, either alone or in combination with G193X Elane, had no effect on basal granulopoiesis. However, inhibition of the ER-associated degradation (ERAD) pathway using a proteosome inhibitor resulted in marked neutropenia in G193X Elane. The selective sensitivity of G913X Elane granulocytic cells to ER stress provides new and strong support for the UPR model of disease patho-genesis in SCN.

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Preservation of circadian rhythms by the protein folding chaperone, BiP

10.1101/348078 ◽

2018 ◽

Author(s):

Adam Pickard ◽

Joan Chang ◽

Nissrin Alachkar ◽

Ben Calverley ◽

Richa Garva ◽

...

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Er Stress ◽

Protein Misfolding ◽

Collagen Synthesis ◽

Oscillation Amplitude ◽

Unfolded Protein ◽

Progression Of Disease ◽

The Unfolded Protein Response ◽

Protein Response

AbstractER stress and dysregulation of collagen synthesis are associated with progression of disease in cancer and fibrosis. Collagen synthesis is co-ordinated with the circadian clock, which curiously in cancer cells, is deregulated by ER stress. We hypothesised that interplay exists between circadian rhythm, collagen synthesis and ER stress in normal cells. Here we show that fibroblasts with ER stress do not demonstrate circadian rhythms in gene expression upon clock-synchronizing time cues. Conversely, overexpression of BiP or treatment with chemical chaperones strengthens the oscillation amplitude of circadian rhythms. The significance of these findings was explored in tendon, where we showed that BiP expression is ramped preemptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, we propose, this forestalls activation of the unfolded protein response in order for circadian rhythms to be maintained. Thus, targeting ER stress could be used to modulate circadian rhythm and restore collagen homeostasis in disease.

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QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis

Science ◽

10.1126/science.abb6896 ◽

2020 ◽

Vol 371 (6524) ◽

pp. eabb6896

Author(s):

Kwontae You ◽

Lingfei Wang ◽

Chih-Hung Chou ◽

Kai Liu ◽

Toru Nakata ◽

...

Keyword(s):

Cell Death ◽

Er Stress ◽

Cell Fate ◽

Protein Misfolding ◽

Transcriptional Control ◽

Stress Protein ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Genome Scale

Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.

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