Unfolded Protein Response

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Peter Walter - One of the best experts on this subject based on the ideXlab platform.

  • structural basis of the Unfolded Protein Response
    Annual Review of Cell and Developmental Biology, 2012
    Co-Authors: Alexei Korennykh, Peter Walter
    Abstract:

    The Unfolded Protein Response (UPR) is a network of intracellular signaling pathways that maintain the Protein-folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells. Dedicated molecular sensors embedded in the ER membrane detect incompletely folded or Unfolded Proteins in the ER lumen and activate a transcriptional program that increases the abundance of the ER according to need. In metazoans the UPR additionally regulates translation and thus relieves Unfolded Protein load by globally reducing Protein synthesis. If homeostasis in the ER cannot be reestablished, the metazoan UPR switches from the prosurvival to the apoptotic mode. The UPR involves a complex, coordinated action of many genes that is controlled by one ER-embedded sensor, Ire1, in yeasts, and three sensors, Ire1, PERK, and ATF6, in higher eukaryotes, including human. We discuss the emerging molecular understanding of the UPR and focus on the structural biology of Ire1 and PERK, the two recently crystallized UPR sensors.

  • the Unfolded Protein Response from stress pathway to homeostatic regulation
    Science, 2011
    Co-Authors: Peter Walter
    Abstract:

    The vast majority of Proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled Proteins advance from the ER to the cell surface. To ascertain fidelity in Protein folding, cells regulate the Protein-folding capacity in the ER according to need. The ER responds to the burden of Unfolded Proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the Unfolded Protein Response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.

  • membrane expansion alleviates endoplasmic reticulum stress independently of the Unfolded Protein Response
    Journal of Cell Biology, 2009
    Co-Authors: Sebastian Schuck, William A Prinz, Kurt S Thorn, Christiane Voss, Peter Walter
    Abstract:

    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.

  • the Unfolded Protein Response signals through high order assembly of ire1
    Nature, 2009
    Co-Authors: Alexei Korennykh, Chao Zhang, Kevan M Shokat, Pascal F Egea, Andrei A Korostelev, Janet Finermoore, Robert M Stroud, Peter Walter
    Abstract:

    Aberrant folding of Proteins in the endoplasmic reticulum activates the bifunctional transmembrane kinase/endoribonuclease Ire1. Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors. This non-conventional mRNA splicing event initiates the Unfolded Protein Response, a transcriptional program that relieves the endoplasmic reticulum stress. Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-A crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.

  • ire1 signaling affects cell fate during the Unfolded Protein Response
    Science, 2007
    Co-Authors: Jonathan H Lin, Douglas Yasumura, Hannah R Cohen, Chao Zhang, Barbara Panning, Kevan M Shokat, Matthew M Lavail, Peter Walter
    Abstract:

    Endoplasmic reticulum (ER) stress activates a set of signaling pathways, collectively termed the Unfolded Protein Response (UPR). The three UPR branches (IRE1, PERK, and ATF6) promote cell survival by reducing misfolded Protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. How the UPR integrates its cytoprotective and proapoptotic outputs to select between life or death cell fates is unknown. We found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and proapoptotic transcription regulator Chop induction, was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa.

Randal J. Kaufman - One of the best experts on this subject based on the ideXlab platform.

  • mechanisms regulation and functions of the Unfolded Protein Response
    Nature Reviews Molecular Cell Biology, 2020
    Co-Authors: Claudio Hetz, Kezhong Zhang, Randal J. Kaufman
    Abstract:

    Cellular stress induced by the abnormal accumulation of Unfolded or misfolded Proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the Unfolded Protein Response (UPR), a signal transduction pathway that senses the fidelity of Protein folding in the ER lumen. The UPR transmits information about Protein folding status to the nucleus and cytosol to adjust the Protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.

  • physiological pathological ramifications of transcription factors in the Unfolded Protein Response
    Genes & Development, 2017
    Co-Authors: Randal J. Kaufman
    Abstract:

    : Numerous environmental, physiological, and pathological insults disrupt Protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the Unfolded Protein Response (UPR), to maintain a productive ER Protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

  • the Unfolded Protein Response in immunity and inflammation
    Nature Reviews Immunology, 2016
    Co-Authors: Joep Grootjans, Randal J. Kaufman, Arthur Kaser, Richard S Blumberg
    Abstract:

    The Unfolded Protein Response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune Response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour Responses.

  • Unfolded Protein Response
    Current Biology, 2012
    Co-Authors: Stewart Siyan Cao, Randal J. Kaufman
    Abstract:

    Summary In eukaryotic cells, the endoplasmic reticulum (ER) is a membrane-enclosed interconnected organelle responsible for the synthesis, folding, modification, and quality control of numerous secretory and membrane Proteins. The processes of Protein folding and maturation are highly assisted and scrutinized but are also sensitive to changes in ER homeostasis, such as Ca 2+ depletion, oxidative stress, hypoxia, energy deprivation, metabolic stimulation, altered glycosylation, activation of inflammation, as well as increases in Protein synthesis or the expression of misfolded Proteins or unassembled Protein subunits. Only properly folded Proteins can traffic to the Golgi apparatus, whereas those that misfold are directed to ER-associated degradation (ERAD) or to autophagy. The accumulation of Unfolded/misfolded Proteins in the ER activates signaling events to orchestrate adaptive cellular Responses. This Unfolded Protein Response (UPR) increases the ER Protein-folding capacity, reduces global Protein synthesis, and enhances ERAD of misfolded Proteins.

  • the impact of the Unfolded Protein Response on human disease
    Journal of Cell Biology, 2012
    Co-Authors: Shiyu Wang, Randal J. Kaufman
    Abstract:

    A central function of the endoplasmic reticulum (ER) is to coordinate Protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/Unfolded Proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the Unfolded Protein Response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory Response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

Claudio Hetz - One of the best experts on this subject based on the ideXlab platform.

  • endoplasmic reticulum stress and Unfolded Protein Response in cardiovascular diseases
    Nature Reviews Cardiology, 2021
    Co-Authors: Claudio Hetz, Jun Ren, James R Sowers, Yingmei Zhang
    Abstract:

    Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of Unfolded or misfolded Proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the Unfolded Protein Response (UPR), a signalling pathway that adjusts the Protein-folding capacity of the cell to sustain the cell’s secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress Response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs. In this Review, Ren and colleagues summarize the latest advances in understanding the Unfolded Protein Response and endoplasmic reticulum stress in the pathogenesis of cardiovascular disease and discuss potential therapeutic strategies aimed at restoring endoplasmic reticulum proteostasis in cardiovascular diseases.

  • mechanisms regulation and functions of the Unfolded Protein Response
    Nature Reviews Molecular Cell Biology, 2020
    Co-Authors: Claudio Hetz, Kezhong Zhang, Randal J. Kaufman
    Abstract:

    Cellular stress induced by the abnormal accumulation of Unfolded or misfolded Proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the Unfolded Protein Response (UPR), a signal transduction pathway that senses the fidelity of Protein folding in the ER lumen. The UPR transmits information about Protein folding status to the nucleus and cytosol to adjust the Protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.

  • the Unfolded Protein Response and cell fate control
    Molecular Cell, 2018
    Co-Authors: Claudio Hetz, Feroz R Papa
    Abstract:

    The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the Protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the Unfolded Protein Response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate. These findings are timely and significant because they inform an evolving mechanistic understanding of a wide variety of human diseases, including diabetes mellitus, neurodegeneration, and cancer, thus opening up the potential for new therapeutic modalities to treat these diverse diseases.

  • er stress and the Unfolded Protein Response in neurodegeneration
    Nature Reviews Neurology, 2017
    Co-Authors: Claudio Hetz, Smita Saxena
    Abstract:

    The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded Proteins in the brain. In physiological conditions, the proteostasis network maintains normal Protein folding, trafficking and degradation; alterations in this network - particularly disturbances to the function of endoplasmic reticulum (ER) - are thought to contribute to abnormal Protein aggregation. ER stress triggers a signalling reaction known as the Unfolded Protein Response (UPR), which induces adaptive programmes that improve Protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.

  • Proteostasis control by the Unfolded Protein Response
    Nature Cell Biology, 2015
    Co-Authors: Claudio Hetz, Eric Chevet, Scott A. Oakes
    Abstract:

    Stress induced by accumulation of misfolded Proteins in the endoplasmic reticulum is observed in many physiological and pathological conditions. To cope with endoplasmic reticulum stress, cells activate the Unfolded Protein Response, a dynamic signalling network that orchestrates the recovery of homeostasis or triggers apoptosis, depending on the level of damage. Here we provide an overview of recent insights into the mechanisms that cells employ to maintain proteostasis and how the Unfolded Protein Response determines cell fate under endoplasmic reticulum stress.

Anni Warri - One of the best experts on this subject based on the ideXlab platform.

  • endoplasmic reticulum stress the Unfolded Protein Response autophagy and the integrated regulation of breast cancer cell fate
    Cancer Research, 2012
    Co-Authors: Robert Clarke, Katherine L Cook, Caroline O B Facey, Iman Tavassoly, Jessica L Schwartz, William T Baumann, John J Tyson, Jianhua Xuan, Yue Wang, Anni Warri
    Abstract:

    How breast cancer cells respond to the stress of endocrine therapies determines whether they will acquire a resistant phenotype or execute a cell-death pathway. After a survival signal is successfully executed, a cell must decide whether it should replicate. How these cell-fate decisions are regulated is unclear, but evidence suggests that the signals that determine these outcomes are highly integrated. Central to the final cell-fate decision is signaling from the Unfolded Protein Response, which can be activated following the sensing of stress within the endoplasmic reticulum. The duration of the Response to stress is partly mediated by the duration of inositol-requiring enzyme-1 activation following its release from heat shock Protein A5. The resulting signals appear to use several B-cell lymphoma-2 family members to both suppress apoptosis and activate autophagy. Changes in metabolism induced by cellular stress are key components of this regulatory system, and further adaptation of the metabolome is affected in Response to stress. Here we describe the Unfolded Protein Response, autophagy, and apoptosis, and how the regulation of these processes is integrated. Central topologic features of the signaling network that integrate cell-fate regulation and decision execution are discussed.

  • endoplasmic reticulum stress the Unfolded Protein Response autophagy and the integrated regulation of breast cancer cell fate
    Cancer Research, 2012
    Co-Authors: Robert Clarke, Katherine L Cook, Caroline O B Facey, Iman Tavassoly, Jessica L Schwartz, William T Baumann, John J Tyson, Jianhua Xuan, Yue Wang, Anni Warri
    Abstract:

    How breast cancer cells respond to the stress of endocrine therapies determines whether they will acquire a resistant phenotype or execute a cell-death pathway. After a survival signal is successfully executed, a cell must decide whether it should replicate. How these cell-fate decisions are regulated is unclear, but evidence suggests that the signals that determine these outcomes are highly integrated. Central to the final cell-fate decision is signaling from the Unfolded Protein Response, which can be activated following the sensing of stress within the endoplasmic reticulum. The duration of the Response to stress is partly mediated by the duration of inositol-requiring enzyme-1 activation following its release from heat shock Protein A5. The resulting signals appear to use several B-cell lymphoma-2 family members to both suppress apoptosis and activate autophagy. Changes in metabolism induced by cellular stress are key components of this regulatory system, and further adaptation of the metabolome is affected in Response to stress. Here we describe the Unfolded Protein Response, autophagy, and apoptosis, and how the regulation of these processes is integrated. Central topologic features of the signaling network that integrate cell-fate regulation and decision execution are discussed. Cancer Res; 72(6); 1321–31. ©2012 AACR .

Cole M Haynes - One of the best experts on this subject based on the ideXlab platform.

  • maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial Unfolded Protein Response
    Nature, 2016
    Co-Authors: Anna M Schulz, Mark W Pellegrino, Cole M Haynes, Yun Lu, Shai Shaham
    Abstract:

    In the context of mitochondrial genome heteroplasmy that causes defective oxidative phosphorylation in C. elegans, the ATFS-1-mediated mitochondrial Unfolded Protein Response maintains the deleterious mitochondrial DNA in an attempt to recover oxidative phosphorylation activity and avoid cellular dysfunction. A eukaryotic cell contains a single copy of the nuclear genome, but hundreds of mitochondrial genomes (mtDNA), encoding Proteins essential for oxidative phosphorylation. The cell can tolerate a number of mutations or deletions in mitochondrial genes, but beyond a toxic threshold, further mutations can cause inborn mitochondrial diseases. Cole Haynes and colleagues examined the mechanism by which mtDNA mutations are tolerated by focusing on the role of the mitochondrial Unfolded Protein Response (UPRmt), a process mediated by the transcription factor ATFS-1 that promotes the recovery of defective mitochondria. They compare normal Caenorhabditis elegans roundworms to a heteroplasmic strain carrying a deletion mutation in four mitochondrial-encoded genes in 60% of the mitochondria. The heteroplasmic strain displayed constant UPRmt activation and only modest mitochondrial dysfunction. In worms with impaired UPRmt activity, there was a tenfold reduction in the number of mutated mtDNAs. The authors infer that ATFS-1-mediated UPRmt maintains the deleterious mtDNA in an attempt to recover oxidative phosphorylation activity, to avoid the possible alternative scenario of the demise of the cell. Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearns–Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells1 and dopaminergic neurons2 during ageing. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OXPHOS dysfunction is by activating the mitochondrial Unfolded Protein Response (UPRmt), a transcriptional Response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria3,4. Here we investigate the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic Caenorhabditis elegans strain that stably expresses wild-type mtDNA and mtDNA with a 3.1-kilobase deletion (∆mtDNA) lacking four essential genes5. The heteroplasmic strain, which has 60% ∆mtDNA, displays modest mitochondrial dysfunction and constitutive UPRmt activation. ATFS-1 impairment reduced the ∆mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPRmt activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.

  • signaling the mitochondrial Unfolded Protein Response
    Biochimica et Biophysica Acta, 2013
    Co-Authors: Mark W Pellegrino, Amrita M Nargund, Cole M Haynes
    Abstract:

    Abstract Mitochondria are compartmentalized organelles essential for numerous cellular functions including ATP generation, iron-sulfur cluster biogenesis, nucleotide and amino acid metabolism as well as apoptosis. To promote biogenesis and proper function, mitochondria have a dedicated repertoire of molecular chaperones to facilitate Protein folding and quality control proteases to degrade those Proteins that fail to fold correctly. Mitochondrial Protein folding is challenged by the complex organelle architecture, the deleterious effects of electron transport chain-generated reactive oxygen species and the mitochondrial genome's susceptibility to acquiring mutations. In Response to the accumulation of Unfolded or misfolded Proteins beyond the organelle's chaperone capacity, cells mount a mitochondrial Unfolded Protein Response (UPR mt ). The UPR mt is a mitochondria-to-nuclear signal transduction pathway resulting in the induction of mitochondrial protective genes including mitochondrial molecular chaperones and proteases to re-establish Protein homeostasis within the mitochondrial Protein-folding environment. Here, we review the current understanding of UPR mt signal transduction and the impact of the UPR mt on diseased cells. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.