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unfolded protein response

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https://www.readbyqxmd.com/read/29330363/disulfide-isomerization-reactions-in-titin-immunoglobulin%C3%A2-domains-enable-a-mode-of-protein-elasticity
#1
David Giganti, Kevin Yan, Carmen L Badilla, Julio M Fernandez, Jorge Alegre-Cebollada
The response of titin to mechanical forces is a major determinant of the function of the heart. When placed under a pulling force, the unstructured regions of titin uncoil while its immunoglobulin (Ig) domains unfold and extend. Using single-molecule atomic force microscopy, we show that disulfide isomerization reactions within Ig domains enable a third mechanism of titin elasticity. Oxidation of Ig domains leads to non-canonical disulfide bonds that stiffen titin while enabling force-triggered isomerization reactions to more extended states of the domains...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29330040/yod1-attenuates-neurogenic-proteotoxicity-through-its-deubiquitinating-activity
#2
Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells...
January 10, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29329780/oncogenic-rac1-and-nras-drive-resistance-to-endoplasmic-reticulum-stress-through-mek-erk-signalling
#3
Michael D Bright, Paul A Clarke, Paul Workman, Faith E Davies
Cancer cells are able to survive under conditions that cause endoplasmic reticulum stress (ER-stress), and can adapt to this stress by upregulating cell-survival signalling pathways and down-regulating apoptotic pathways. The cellular response to ER-stress is controlled by the unfolded protein response (UPR). Small Rho family GTPases are linked to many cell responses including cell growth and apoptosis. In this study, we investigate the function of small GTPases in cell survival under ER-stress. Using siRNA screening we identify that RAC1 promotes cell survival under ER-stress in cells with an oncogenic N92I RAC1 mutation...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29329521/treating-c3-glomerulopathy-with-eculizumab
#4
Thomas Welte, Frederic Arnold, Julia Kappes, Maximilian Seidl, Karsten Häffner, Carsten Bergmann, Gerd Walz, Elke Neumann-Haefelin
BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab...
January 12, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29329354/palmitate-induced-er-stress-and-inhibition-of-protein-synthesis-in-cultured-myotubes-does-not-require-toll-like-receptor-4
#5
Ben D Perry, Jill A Rahnert, Yang Xie, Bin Zheng, Myra E Woodworth-Hobbs, S Russ Price
Saturated fatty acids, such as palmitate, are elevated in metabolically dysfunctional conditions like type 2 diabetes mellitus. Palmitate has been shown to impair insulin sensitivity and suppress protein synthesis while upregulating proteolytic systems in skeletal muscle. Increased sarco/endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response may contribute to the palmitate-induced impairment of muscle protein synthesis. In some cell types, ER stress occurs through activation of the Toll-like receptor 4 (TLR4)...
2018: PloS One
https://www.readbyqxmd.com/read/29328657/molecular-mechanism-of-protein-unfolding-under-shear-a-lattice-boltzmann-molecular-dynamics-study
#6
Fabio Sterpone, Philippe Derreumaux, Simone Melchionna
Proteins are marginally stable soft-matter entities that can be disrupted using a variety of perturbative stresses, including thermal, chemicals or mechanical ones. Fluid under extreme flow conditions is a possible route to probe the weakness of biomolecules and collect information on the molecular cohesive interactions that secure their stability. Moreover, in many cases, physiological flow triggers the functional response of specialised proteins as occurring in blood coagulation or cell adhesion. In this paper, we deploy the Lattice Boltzmann Molecular Dynamics technique based on the coarse grained model for protein OPEP, to study the mechanism of protein unfolding under Couette flow...
January 12, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29328656/design-and-synthesis-of-novel-reactive-oxygen-species-inducers-for-the-treatment-of-pancreatic-ductal-adenocarcinoma
#7
Yuting Kuang, Mario Sechi, Salvatore Nurra, Mats Ljungman, Nouri Neamati
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323786/pulmonary-endoplasmic-reticulum-stress-scars-smoke-and-suffocation
#8
REVIEW
Jennifer A Dickens, Elke Malzer, Joseph E Chambers, Stefan J Marciniak
Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response (UPR) and/or the integrated stress response (ISR). Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress...
January 11, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29323465/multiplexed-digital-mrna-expression-analysis-profiles-system-wide-changes-in-mrna-abundance-and-responsiveness-of-upr-specific-gene-expression-changes-during-batch-culture-of-recombinant-chinese-hamster-ovary-cells
#9
Rodrigo Maldonado-Agurto, Alan J Dickson
The unfolded protein response (UPR) signalling pathway is viewed as critical for setting the effectiveness of recombinant protein expression in CHO cells. In this study, we used Nanostring nCounter technology to study expression of a group of genes associated with cellular processes linked to UPR activation under ER stress and the changing environment of a batch culture. Time course induction of ER stress, using tunicamycin (TM), showed a group of genes such as Chop, Trb3, Sqstm1, Grp78 and Herpud1 responded rapidly to TM inhibition of N-glycosylation, whilst others such as Atf5, Odz4 and Birc5 exhibited a delayed response...
January 11, 2018: Biotechnology Journal
https://www.readbyqxmd.com/read/29323257/dengue-virus-induced-er-stress-is-required-for-autophagy-activation-viral-replication-and-pathogenesis-both-in-vitro-and-in-vivo
#10
Ying-Ray Lee, Szu-Han Kuo, Ching-Yen Lin, Po-Jung Fu, Yee-Shin Lin, Trai-Ming Yeh, Hsiao-Sheng Liu
Dengue virus (DENV) utilizes the endoplasmic reticulum (ER) for replication and assembling. Accumulation of unfolded proteins in the ER lumen leads to ER stress and unfolded protein response (UPR). Three branches of UPRs temporally modulated DENV infection. Moreover, ER stress can also induce autophagy. DENV infection induces autophagy which plays a promotive role in viral replication has been reported. However, the role of ER stress in DENV-induced autophagy, viral titer, and pathogenesis remain unclear. Here, we reveal that ER stress and its downstream UPRs are indispensable for DENV-induced autophagy in various human cells...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321322/dengue-virus-selectively-annexes-endoplasmic-reticulum-associated-translation-machinery-as-a-strategy-for-co-opting-host-cell-protein-synthesis
#11
David W Reid, Rafael K Campos, Jessica R Child, Tianli Zheng, Kitti Wing Ki Chan, Shelton S Bradrick, Subhash G Vasudevan, Mariano A Garcia-Blanco, Christopher V Nicchitta
A primary question in Dengue virus (DENV) biology is the molecular strategy for recruitment of host cell protein synthesis machinery. Here we combined cell fractionation, ribosome profiling, and RNA-seq to investigate the subcellular organization of viral genome translation and replication as well as host cell translation and its response to DENV infection. We report that throughout the viral life cycle, DENV (+) and (-) strand RNAs were highly partitioned to the endoplasmic reticulum (ER), identifying the ER as the primary site of DENV translation...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29320742/defective-mitochondrial-trna-taurine-modification-activates-global-proteostress-and-leads-to-mitochondrial-disease
#12
Md Fakruddin, Fan-Yan Wei, Takeo Suzuki, Kana Asano, Takashi Kaieda, Akiko Omori, Ryoma Izumi, Atsushi Fujimura, Taku Kaitsuka, Keishi Miyata, Kimi Araki, Yuichi Oike, Luca Scorrano, Tsutomu Suzuki, Kazuhito Tomizawa
A subset of mitochondrial tRNAs (mt-tRNAs) contains taurine-derived modifications at 34U of the anticodon. Loss of taurine modification has been linked to the development of mitochondrial diseases, but the molecular mechanism is still unclear. Here, we showed that taurine modification is catalyzed by mitochondrial optimization 1 (Mto1) in mammals. Mto1 deficiency severely impaired mitochondrial translation and respiratory activity. Moreover, Mto1-deficient cells exhibited abnormal mitochondrial morphology owing to aberrant trafficking of nuclear DNA-encoded mitochondrial proteins, including Opa1...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29317503/er-stress-mobilization-of-death-associated-protein-kinase-1-dependent-xenophagy-counteracts-mitochondria-stress-induced-epithelial-barrier-dysfunction
#13
Fernando Lopes, Åsa V Keita, Alpana Saxena, Jose Luis Reyes, Nicole Mancini, Ala Al Rajabi, Arthur Wang, Cristiane Baggio, Michael Dicay, Rob van Dalen, Younghee Ahn, Matheus Carneiro, Nathan Peters, Jong M Rho, Wallace MacNaughton, Stephan E Girardin, Humberto Jijon, Dana J Philpott, Johan D Söderholm, Derek M McKay
The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin, and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria...
January 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29316442/circadian-clocks-and-upr-new-twists-as-the-story-unfolds
#14
Nikolay B Milev, David Gatfield
Circadian clocks help control the unfolded protein response (UPR). In a recent issue of Nature Cell Biology, Bu et al. (2017) show that the interaction is reciprocal, with miRNA-211 providing a signal from the UPR to the clock component BMAL1, affecting circadian timing, global translational control, and cancer cell survival.
January 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29316036/inhibition-of-ire1-results-in-decreased-scar-formation
#15
Tatiana V Boyko, Rakesh Bam, Dadi Jiang, Zhen Wang, Namrata Bhatia, Misha C Tran, Michael T Longaker, Albert C Koong, George P Yang
Wound healing is characterized by the production of large amounts of protein necessary to replace lost cellular mass and extracellular matrix. The unfolded protein response (UPR) is an important adaptive cellular response to increased protein synthesis. One of the main components of the UPR is IRE1, an ER transmembrane protein with endonuclease activity that produces the activated form of the transcription factor XBP1. Using luciferase reporter mice for Xbp1 splicing, we showed that IRE1 was up-regulated during excisional wound healing at the time in wound healing consistent with that of the proliferative phase, when the majority of protein synthesis for cellular proliferation and matrix deposition occurs...
January 8, 2018: Wound Repair and Regeneration
https://www.readbyqxmd.com/read/29315487/using-extensional-flow-to-reveal-diverse-aggregation-landscapes-for-three-igg1-molecules
#16
Leon F Willis, Amit Kumar, John Dobson, Nick Bond, David Lowe, Richard Turner, Sheena E Radford, Nikil Kapur, David J Brockwell
Monoclonal antibodies (mAbs) currently dominate the biopharmaceutical sector due to their potency and efficacy against a range of disease targets. These proteinaceous therapeutics are, however, susceptible to unfolding, mis-folding and aggregation by environmental perturbations. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation and storage. Hydrodynamic forces have also been linked to aggregation, but the ability of different flow fields (e.g. shear and extensional flow) to trigger aggregation has remained unclear...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29314493/in-vitro-efficacy-of-a-first-generation-valosin-containing-protein-inhibitor-cb-5083-against-canine-lymphoma
#17
A Gareau, C Rico, D Boerboom, M-E Nadeau
Valosin-containing protein (VCP), through its critical role in the maintenance of protein homeostasis, is a promising target for the treatment of several malignancies, including canine lymphoma. CB-5083, a first-in-class VCP inhibitor, exerts cytotoxicity through the induction of irreversible proteotoxic stress and possesses a broad spectrum of anticancer activity. Here, we determined the cytotoxicity CB-5083 in canine lymphoma cells and its mechanism of action in vitro. Canine lymphoma cell lines were treated with varying concentrations of CB-5083 and assessed for viability by trypan blue exclusion and apoptosis by caspase activity assays...
January 4, 2018: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/29311669/adipocyte-activated-oxidative-and-er-stress-pathways-promote-tumor-survival-in-bone-via-upregulation-of-heme-oxygenase-1-and-survivin
#18
Mackenzie K Herroon, Erandi Rajagurubandara, Jonathan D Diedrich, Elisabeth I Heath, Izabela Podgorski
Metastatic tumor cells engage the local tumor microenvironment and activate specific pro-survival mechanisms to thrive and progress in the harsh bone marrow niche. Here we show that the major contributors to the survival of carcinoma cells that have colonized the bone marrow are the adipocyte-induced oxidative stress and ER stress pathways. We demonstrate that upon exposure to adipocyte-rich environments in vitro or in vivo, bone-trophic prostate and breast tumor cells upregulate the oxidative stress enzyme, HO-1...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29306025/silver-nanoparticles-induce-sh-sy5y-cell-apoptosis-via-endoplasmic-reticulum-and-mitochondrial-pathways-that-lengthen-endoplasmic-reticulum-mitochondria-contact-sites-and-alter-inositol-3-phosphate-receptor-function
#19
Lin Li, Jiahui Cui, Zi Liu, Xuejiao Zhou, Zengqiang Li, Yang Yu, Yuanyuan Jia, Daiying Zuo, Yingliang Wu
Silver nanoparticles (AgNPs) have many medical and commercial applications, but their effects on human health are poorly understood. The aim of this study was to assess the effect of AgNPs on the human neuroblastoma cell line SH-SY5Y and to explore their potential mechanisms of action. We found that AgNPs decreased SH-SY5Y cell viability in a dose- and time-dependent manner. Exposure to AgNPs activated endoplasmic reticulum (ER) stress, as reflected by upregulated expression of glucose-regulated protein 78 (GRP78), phosphorylated PKR-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), C/EBP homology protein (CHOP), spliced X-box binding protein-1 (XBP1), and phosphorylated inositol-requiring enzyme (p-IRE), all of which are involved in the cellular unfolded protein response...
January 3, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29305604/molecular-defects-of-the-disease-causing-human-arrestin-1-c147f-mutant
#20
Sergey A Vishnivetskiy, Lori S Sullivan, Sara J Bowne, Stephen P Daiger, Eugenia V Gurevich, Vsevolod V Gurevich
Purpose: The purpose of this study was to identify the molecular defect in the disease-causing human arrestin-1 C147F mutant. Methods: The binding of wild-type (WT) human arrestin-1 and several mutants with substitutions in position 147 (including C147F, which causes dominant retinitis pigmentosa in humans) to phosphorylated and unphosphorylated light-activated rhodopsin was determined. Thermal stability of WT and mutant human arrestin-1, as well as unfolded protein response in 661W cells, were also evaluated...
January 1, 2018: Investigative Ophthalmology & Visual Science
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