HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum

Gene, Journal Year: 2017, Volume and Issue: 618, P. 14 - 23

Published: March 7, 2017

Language: Английский

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GRP78 at the Centre of the Stage in Cancer and Neuroprotection

Frontiers in Neuroscience, Journal Year: 2017, Volume and Issue: 11

Published: April 5, 2017

The 78-kDa glucose-regulated protein GRP78, also known as BiP and HSP5a, is a multifunctional with activities far beyond its well-known role in the unfolded response (UPR) which activated after endoplasmic reticulum (ER) stress cells. Most of these newly discovered depend on position within cell. GRP78 located mainly ER, but it has been observed cytoplasm, mitochondria, nucleus, plasma membrane secreted, although dedicated mostly to engage endogenous cytoprotective processes. Hence, may control either UPR macroautophagy or phosphatidylinositol 3-kinase (PI3K)/AKT pro-survival pathways. influences how tumour cells survive, proliferate, develop chemoresistance. In neurodegeneration, mechanisms neuroprotection are frequently insufficient dysregulated. Lessons from biology give us clues about boosting neuroprotective age-related neurodegeneration. Herein, functions revealed at centre stage apparently opposite sites same coin regarding cytoprotection: neurodegeneration cancer. goal comprehensive critical review that serve guide future experiments identify interventions will enhance neuroprotection.

Language: Английский

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Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Frontiers in Cell and Developmental Biology, Journal Year: 2017, Volume and Issue: 5

Published: May 9, 2017

Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of genes induced UPR are rather well established, open questions remain including the precise role human diseases interactions between sensor systems during signaling. Particularly, issue how normally adaptive pro-survival turns into deleterious process causing sustained endoplasmic reticulum (ER) death requires more studies. also named friend with multiple personalities that we need understand better fully recognize its normal physiology pathology. interacts other organelles mitochondria, signals degradation pathways such as autophagy ubiquitin proteasome system. Here review current concepts mechanisms studied cells model highlight relevance related various diseases.

Language: Английский

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Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells

Journal of Biological Chemistry, Journal Year: 2018, Volume and Issue: 293(30), P. 11709 - 11726

Published: June 10, 2018

Coronavirus tropism is predominantly determined by the interaction between coronavirus spikes and host receptors. In this regard, coronaviruses have evolved a complicated receptor-recognition system through their spike proteins. Spikes from highly related can recognize distinct receptors, whereas of distant employ same cell-surface molecule for entry. Moreover, broad range molecules in addition to receptors thereby augment attachment or The receptor Middle East respiratory syndrome (MERS-CoV) dipeptidyl peptidase 4 (DPP4). study, we identified membrane-associated 78-kDa glucose-regulated protein (GRP78) as an additional binding target MERS-CoV spike. Further analyses indicated that GRP78 could not independently render nonpermissive cells susceptible infection but facilitate entry into permissive augmenting virus attachment. More importantly, exploring potential interactions other coronaviruses, discovered conserved human interact with bat HKU9 (bCoV-HKU9) its cell surface. Taken together, our study has factor proteins two Betacoronaviruses, lineage C D bCoV-HKU9. capacity surface both phylogenetically exemplifies need continuous surveillance evolution animal monitor adaptations.

Language: Английский

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The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100759 - 100759

Published: Jan. 1, 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 global pandemic, utilizes host receptor angiotensin-converting enzyme (ACE2) for viral entry. However, other factors might also play important roles in SARS-CoV-2 infection, providing new directions antiviral treatments. GRP78 is a stress-inducible chaperone entry and infectivity many viruses. Recent molecular docking analyses revealed putative interaction between receptor-binding domain (RBD) Spike protein (SARS-2-S). Here we report that can form complex with SARS-2-S ACE2 on surface at perinuclear region typical endoplasmic reticulum VeroE6-ACE2 cells substrate-binding critical this interaction. In vitro binding studies further confirmed directly bind to RBD ACE2. To investigate role complex, knocked down cells. Loss markedly reduced cell expression led activation markers unfolded response. Treatment lung epithelial humanized monoclonal antibody (hMAb159) selected its safe clinical profile preclinical models depleted expression, as well SARS-2-S-driven infection vitro. Our data suggest an auxiliary factor potential target combat novel pathogen viruses utilize combination therapy.

Language: Английский

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Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt Activation

Circulation Research, Journal Year: 2018, Volume and Issue: 122(11), P. 1545 - 1554

Published: April 18, 2018

Rationale: Restoration of coronary artery blood flow is the most effective means ameliorating myocardial damage triggered by ischemic heart disease. However, reperfusion elicits an increment additional injury to myocardium. Accumulating evidence indicates that unfolded protein response (UPR) in cardiomyocytes activated ischemia/reperfusion (I/R) injury. Xbp1s (spliced X-box binding 1), highly conserved branch response, protective cardiac I/R GRP78 (78 kDa glucose-regulated protein), a master regulator UPR and target, upregulated after I/R. its role during remains largely undefined. Objective: To elucidate cardiomyocyte using both vitro vivo approaches. Methods Results: Simulated cultured neonatal rat ventricular myocytes induced apoptotic cell death strong activation GRP78. Overexpression significantly protected from I/R-induced death. Furthermore, cardiomyocyte-specific overexpression ameliorated vivo. Exploration underlying mechanisms revealed mitigates cellular suppressing accumulation reactive oxygen species. We go on show GRP78-mediated cytoprotective involves plasma membrane translocation interaction with PI3 kinase, culminating stimulation Akt. This required as inhibition Akt pathway blunted antioxidant activity cardioprotective effects Conclusions: induction stimulates signaling protects against oxidative stress, which together protect cells damage.

Language: Английский

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GRP78 Is an Important Host Factor for Japanese Encephalitis Virus Entry and Replication in Mammalian Cells

Journal of Virology, Journal Year: 2017, Volume and Issue: 91(6)

Published: Jan. 5, 2017

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the leading cause of viral in Southeast Asia with potential to become global pathogen. Here, we identify glucose-regulated protein 78 (GRP78) as an important host for entry and replication. Using plasma membrane fractions from mouse neuronal (Neuro2a) cells, mass spectroscopy analysis identified GRP78 interacting recombinant JEV envelope domain III. was found be expressed on membranes Neuro2a primary neurons, human epithelial Huh-7 cells. Antibodies against significantly inhibited all three cell types, suggesting role entry. Depletion by small interfering RNA (siRNA) blocked into further supporting its uptake. Immunofluorescence studies showed extensive colocalization virus-infected This interaction also confirmed immunoprecipitation studies. Additionally, shown have replication, treatment cells post-virus subtilase cytotoxin that specifically cleaved led substantial reduction replication synthesis, resulting reduced extracellular titers. Our results indicate GRP78, endoplasmic reticulum chaperon HSP70 family, novel factor involved at multiple steps life cycle could therapeutic target.IMPORTANCE Recent years seen rapid spread diseases caused flaviviruses. The flavivirus family includes West Nile, dengue, encephalitis, Zika viruses, which are major threats public health pathogens. several parts Asia, affecting predominantly pediatric population high mortality rate. study focused identification crucial factors targeted cripple infection ultimately lead development effective antivirals. We cellular protein, plays dual two cycle, thus target.

Language: Английский

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The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Frontiers in Molecular Neuroscience, Journal Year: 2017, Volume and Issue: 10

Published: March 20, 2017

The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to plasma membrane through a glycosyl-phosphatydil inositol anchor. Misfolding of PrPC associated with transmissible spongiform encephalopathies, whereas its normal conformer serves as receptor for oligomers β-amyloid peptide, which play major role in pathogenesis Alzheimer's Disease. highly expressed both nervous and immune systems, well other organs, but functions are controversial. Extensive experimental work disclosed multiple physiological roles molecular, cellular systemic levels, affecting homeostasis copper, neuroprotection, stem renewal, memory mechanisms, among others. Often each such process has been heralded bona fide function PrPC, despite restricted attention paid selected phenotypic trait, either modulation gene expression or engagement single ligand. In contrast, inositol-anchored protein was shown bind several extracellular transmembrane ligands, required endow that ability various signal transduction. addition, differing sets those ligands available type- context-dependent scenarios. To account properties, we proposed dynamic platform assembly signaling modules widespread consequences physiology behavior. current review advances hypothesis biological surface scaffold protein, based on striking similarities functional properties proteins involved organization intracellular transduction pathways. Those are: recruit spatially binding molecules specific signaling; mediation crosstalk pathways; reciprocal allosteric regulation partners; compartmentalized responses; dependence upon posttranslational modification; stoichiometric requirements and/or oligomerization-dependent impact signaling. concept may contribute novel approaches development effective treatments hitherto incurable neurodegenerative diseases, informed protein-ligand interactions.

Language: Английский

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Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum

Archives of Biochemistry and Biophysics, Journal Year: 2016, Volume and Issue: 617, P. 106 - 119

Published: Nov. 24, 2016

Language: Английский

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Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-β signaling

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(18)

Published: April 13, 2018

Significance Endoplasmic reticulum (ER) stress-mediated relocalization of ER chaperones to the cell surface allows cells expand their functionality beyond ER, impacting survival, death, migration, and immunity. However, little is known about underlying mechanisms interacting partners on surface. Both protooncogene tyrosine-protein kinase SRC TGF-β are important players in signaling, growth, apoptosis, survival. Our discoveries that activation driving force escape luminal proteins via disruption retrograde transport provide an oncogenic function for uncover a mechanism regulation signaling GRP78/CD109 partnership, with therapeutic implications cancer other human diseases.

Language: Английский

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