Signal integration in the endoplasmic reticulum unfolded protein response
Nature Reviews Molecular Cell BiologyPublished 14 June 2007
David Ron, Peter Walter
Citations6,283
SJR quartileQ1
SJR score37.35
SNIP20.23
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
Abstract
Owing to the toxic potential of unfolded proteins, their accumulation in the endoplasmic reticulum activates a cellular stress response. This unfolded protein response remodels the secretory pathway to accommodate the load of unfolded proteins or, if the burden is insurmountable, promotes cell death to protect the organism. The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways — cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
CellXBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor
4,053 Citations2001Hiderou Yoshida, Toshie Matsui +3 more
The transcription factor XBP1, a target of ATF6, is identified as a mammalian substrate of such an unconventional mRNA splicing system and it is shown that only the spliced form of X BP1 can activate the UPR efficiently.
ScienceProapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
3,945 Citations2001Michael C. Wei, Wei‐Xing Zong +8 more
ScienceEndoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
3,827 Citations2004Umut Özcan, Qiong Cao +8 more
It is shown that obesity causes endoplasmic reticulum (ER) stress, which leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptors substrate–1 (IRS-1).
Molecular CellAn Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
3,314 Citations2003Heather P. Harding, Yuhong Zhang +13 more
A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
NatureProtein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
3,312 Citations1999Heather P. Harding, Yuhong Zhang +1 more
The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
NatureCaspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β
3,262 Citations2000Toshiyuki Nakagawa, Hong Zhu +5 more
It is shown that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals, which may contribute to amyloid-β neurotoxicity.
Molecular CellRegulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells
3,241 Citations2000Heather P. Harding, Isabel Novoa +5 more
Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis, resulting in the induction of the downstream gene CHOP (GADD153).
Annual Review of BiochemistryTHE MAMMALIAN UNFOLDED PROTEIN RESPONSE
3,020 Citations2005Martin Schröder, Randal J. Kaufman
ScienceCoupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1
2,964 Citations2000Fumihiko Urano, Xiao-Zhong Wang +5 more
Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs), and Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and I RE1alpha-/- fibroblasts were impaired in JNK activation by ER stress.
NatureIRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA
2,862 Citations2002Marcella A. Calfon, Huiqing Zeng +6 more
It is demonstrated that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans, suggesting that physiological ER load regulates a developmental decision in higher eukaryotes.
Nature Cell BiologyDynamic interaction of BiP and ER stress transducers in the unfolded-protein response
2,860 Citations2000Anne Bertolotti, Yuhong Zhang +3 more
It is shown that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenAL domains form a stable complex with the ER chaperone BiP.
ScienceChemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
2,414 Citations2006Umut Özcan, Erkan Yılmaz +6 more
It is demonstrated that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.
Molecular Biology of the CellMammalian Transcription Factor ATF6 Is Synthesized as a Transmembrane Protein and Activated by Proteolysis in Response to Endoplasmic Reticulum Stress
2,043 Citations1999Kyosuke Haze, Hiderou Yoshida +3 more
It is proposed that ER stress-induced proteolysis of membrane-bound p90 ATF6 releases soluble p50ATF6, leading to induced transcription in the nucleus, similar to that reported for cholesterol homeostasis.
Molecular CellPerk Is Essential for Translational Regulation and Cell Survival during the Unfolded Protein Response
2,008 Citations2000Heather P. Harding, Yuhong Zhang +3 more
CellFunctional and Genomic Analyses Reveal an Essential Coordination between the Unfolded Protein Response and ER-Associated Degradation
1,997 Citations2000Kevin Travers, Christopher K. Patil +4 more
The unfolded protein response and ERAD are dynamic responses required for the coordinated disposal of misfolded proteins even in the absence of acute stress.
Genes & DevelopmentCHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum
1,993 Citations1998Hélène Zinszner, Masahiko Kuroda +6 more
Compared with the wild type, mouse embryonic fibroblasts derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function, and the proximal tubule epithelium of chop -/+ animals exhibited fourfold lower levels of TUNEL-positive cells, and significantly less evidence for subsequent regeneration.
Genes & DevelopmentCHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
1,989 Citations2004Stefan J. Marciniak, Chi Young Yun +7 more
This work finds that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells, and protects cells from ER stress by decreasing client protein load and changing redox conditions within the organelle.
Molecular and Cellular BiologyGadd153 Sensitizes Cells to Endoplasmic Reticulum Stress by Down-Regulating Bcl2 and Perturbing the Cellular Redox State
1,873 Citations2001Karen D. McCullough, Jennifer L. Martindale +3 more
Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bcl2 and enhanced oxidant injury and protected cells from ER stress-induced cell death.
Molecular CellER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs
1,843 Citations2000Jin Ye, Robert B. Rawson +6 more
It is shown that S1P and S2P are required for the ER stress response as well as for lipid synthesis, and ATF6 processing did not require SCAP, which is essential for SREBP processing.
Proceedings of the National Academy of SciencesReinitiation involving upstream ORFs regulates <i>ATF4</i> mRNA translation in mammalian cells
1,715 Citations2004Krishna M. Vattem, Ronald C. Wek
The results suggest that the mechanism of translation reinitiation involving uORFs is conserved from yeast to mammals.
Developmental CellER Stress Regulation of ATF6 Localization by Dissociation of BiP/GRP78 Binding and Unmasking of Golgi Localization Signals
1,440 Citations2002Jingshi Shen, Xi Chen +2 more
It is found that the ER chaperone BiP/GRP78 binds ATF6 and dissociates in response to ER stress and that dissociation of BiP during ER stress allows ATF6 to be transported to the Golgi.
NatureHsp90 as a capacitor of phenotypic variation
1,418 Citations2002Christine Queitsch, Todd A. Sangster +1 more
ScienceA Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress
1,405 Citations2005Michael Boyce, Kevin F. Bryant +9 more
Salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events and suggests that selective chemical inhibitors of eIF2α deph phosphorylation may be useful in diseases involving ER stress or viral infection.
The Journal of Cell BiologyFeedback Inhibition of the Unfolded Protein Response by <i>GADD34</i>-Mediated Dephosphorylation of eIF2α
1,373 Citations2001Isabel Novoa, Huiqing Zeng +2 more
Findings implicate GADD34-mediated dephosphorylation of eIF2α in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.
ScienceBAX and BAK Regulation of Endoplasmic Reticulum Ca <sup>2+</sup> : A Control Point for Apoptosis
1,373 Citations2003Luca Scorrano, Scott A. Oakes +5 more
BAX and BAK operate in both the ER and mitochondria as an essential gateway for selected apoptotic signals, and targeting of BAX to mitochondria selectively restored apoptosis to “BH3-only” signals.
Molecular CellTranslational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
1,346 Citations2001Donalyn Scheuner, Benbo Song +7 more
It is demonstrated that regulation of translation through eIF2alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.
Genes & DevelopmentASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats
1,334 Citations2002Hideki Nishitoh, Atsushi Matsuzawa +7 more
It is suggested that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.
NatureThe presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins
1,310 Citations1988Yasunori Kozutsumi, Mark S. Segal +3 more
Testing the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin in simian cells shows that malfoldingper se, rather than abnormal glycosylation1, is the proximal inducer of this family of stress proteins.
ScienceDecay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response
1,302 Citations2006Julie Hollien, Jonathan S. Weissman
It is reported that IRE1 independently mediates the rapid degradation of a specific subset of mRNAs, based both on their localization to the ER membrane and on the amino acid sequence they encode, which is well suited to complement other UPR mechanisms.
NaturePlasma cell differentiation requires the transcription factor XBP-1
1,287 Citations2001Andreas Reimold, Neal N. Iwakoshi +8 more
XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium, and when introduced into B-lineage cells, XBP- 1 initiated plasma- cell differentiation.
The EMBO JournalOligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
1,256 Citations1996Caroline E. Shamu, Peter Walter
Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
CellTranscriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase
1,234 Citations1993Jeffery S. Cox, Caroline E. Shamu +1 more
IRE1 encodes a transmembrane serine/threonine kinase that it is proposed transmits the unfolded protein signal across the ER or inner nuclear membrane, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
Molecular CellDiabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk−/− Mice Reveals a Role for Translational Control in Secretory Cell Survival
1,213 Citations2001Heather P. Harding, Huiqing Zeng +6 more
Findings suggest a special role for translational control in protecting secretory cells from ER stress in diabetes mellitus and exocrine pancreatic insufficiency.
The Journal of Cell BiologyCross-Talk between Two Cysteine Protease Families
1,153 Citations2000Toshiyuki Nakagawa, Junying Yuan
It is proposed that disturbance to intracellular calcium storage as a result of ischemic injury or amyloid β peptide cytotoxicity may induce apoptosis through calpain- mediated caspase-12 activation and Bcl-xL inactivation, suggesting a novel apoptotic pathway involving calcium-mediated calpain activation and cross-talks between calpain and caspases families.
ImmunityXBP1, Downstream of Blimp-1, Expands the Secretory Apparatus and Other Organelles, and Increases Protein Synthesis in Plasma Cell Differentiation
1,040 Citations2004Arthur L. Shaffer, Miriam A. Shelef +15 more
XBP1 coordinates diverse changes in cellular structure and function resulting in the characteristic phenotype of professional secretory cells, and upregulates genes encoding many secretory pathway components.
CellA Novel Mechanism for Regulating Activity of a Transcription Factor That Controls the Unfolded Protein Response
1,025 Citations1996Jeffery S. Cox, Peter Walter
It is proposed that the complex regulation of Hac1p expression serves to provide multiple levels at which the UPR can be controlled.
PLoS BiologyAutophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response
1,006 Citations2006Sebastián Bernales, Kent McDonald +1 more
The ER-specific autophagic process described utilizes several autophagy genes: they are induced by the UPR and are essential for the survival of cells subjected to severe ER stress, indicating that ER sequestration into autophagosome-like structures, rather than their degradation, is the important step.
The Journal of Cell BiologyTranslation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response
993 Citations2004Phoebe D. Lu, Heather P. Harding +1 more
Mutation analysis of the ATF4 mRNA revealed that scanning ribosomes initiate translation efficiently at both uORFs and Ribosomes that had translated uORF1 efficiently reinitiate translation at downstream AUGs, common to regulated translation of GCN4 in yeast.
Journal of Biological ChemistryEndoplasmic Reticulum Stress Triggers Autophagy
949 Citations2006Tomohiro Yorimitsu, Usha Nair +2 more
The results indicate that ER stress can induce an autophagic response, and it is found that Atg1 had high kinase activity during ER stress-induced autophagy.
CellThe Transmembrane Kinase Ire1p Is a Site-Specific Endonuclease That Initiates mRNA Splicing in the Unfolded Protein Response
904 Citations1997Carmela Sidrauski, Peter Walter
It is shown that Ire1p is a bifunctional enzyme: in addition to being a kinase, it is a site-specific endoribonuclease that cleaves HAC1 mRNA specifically at both splice junctions and the addition of purified tRNA ligase completes splicing.
Nature Cell BiologyThe endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages
869 Citations2003Bo Feng, Pin Mei Yao +11 more
It is proposed that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.
Journal of Clinical InvestigationTargeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes
866 Citations2002Seiichi Oyadomari, Akio Koizumi +5 more
It is concluded that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction and a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER is suggested.
Journal of Biological ChemistryActivation of Caspase-12, an Endoplastic Reticulum (ER) Resident Caspase, through Tumor Necrosis Factor Receptor-associated Factor 2-dependent Mechanism in Response to the ER Stress
865 Citations2001Takunari Yoneda, Kazunori Imaizumi +5 more
Results indicate that TRAF2 plays crucial roles not only in the signaling of the c-Jun N-terminal kinase pathway but also in activation of caspase-12 to transduce signals from IRE1s, providing a missing link in the ER stress-induced apoptosis-signaling pathway.
CellA transmembrane protein with a cdc2+CDC28-related kinase activity is required for signaling from the ER to the nucleus
821 Citations1993Kazutoshi Morl, Wenzhen Ma +2 more
It is postulated that Ern1p is the proximal sensor of events in the ER and that binding of ligand causes transduction of information across the ER membrane, leading to activation of a specific set of transcription factors.
CellEndoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response
815 Citations2006Kezhong Zhang, Xiaohua Shen +6 more
The studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response.
PLoS BiologyAdaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins
793 Citations2006D. Thomas Rutkowski, Stacey Arnold +8 more
This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt and underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome.
Journal of Clinical InvestigationTargeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes
742 Citations2002Seiichi Oyadomari, Akio Koizumi +5 more
Nature reviews. CancerThe role of the unfolded protein response in tumour development: friend or foe?
709 Citations2004Yanjun Ma, Linda M. Hendershot
Recent delineation of the components of this response indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.
The EMBO JournalER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
707 Citations2005Meixia Bi, Christine Naczki +14 more
It is demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress and suggests that this pathway is an attractive target for antitumor modalities.
Molecular and Cellular BiologyRegulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α
685 Citations2002Constantinos Koumenis, Christine Naczki +6 more
Results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2α and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
NatureQuality control in the endoplasmic reticulum protein factory
678 Citations2003Roberto Sitia, Ineke Braakman
The endoplasmic reticulum (ER) is a factory where secretory proteins are manufactured, and where stringent quality-control systems ensure that only correctly folded proteins are sent to their final destinations.
Developmental CellA Time-Dependent Phase Shift in the Mammalian Unfolded Protein Response
670 Citations2003Hiderou Yoshida, Toshie Matsui +4 more
It is shown here that degradation of misfolded glycoprotein substrates requires transcriptional induction of EDEM (ER degradation-enhancing alpha-mannosidase-like protein), and that this is mediated specifically by IRE1-XBP1 and not by ATF6.
ScienceProapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1α
661 Citations2006Claudio Hetz, Paula Bernasconi +9 more
BAX and BAK function at the ER membrane to activate IRE1α signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.
The Journal of Cell BiologyXBP1
649 Citations2004Rungtawan Sriburi, Suzanne Jackowski +2 more
It is reported that enforced expression of XBP1(S) is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane, and this data suggest that XBP2(S), the active form of the XBP 1 transcription factor generated by UPR-mediated splicing of X BP1 mRNA, links the mammalian UPR to phospholIPid biosynthesis and ER biogenesis.
Molecular and Cellular BiologyTranslational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2
634 Citations2004Jing Deng, Phoebe D. Lu +6 more
Pulse-chase labeling experiments indicate that repression of IκBα translation plays an important role in NF-κB activation in cells experiencing high levels of eIF2α phosphorylation, and suggest a direct role for eif2αosphorylation-dependent translational control in activating NF-kkB during ER stress.
Proceedings of the National Academy of SciencesOn the mechanism of sensing unfolded protein in the endoplasmic reticulum
577 Citations2005Joel J. Credle, Janet Finer-Moore +3 more
It is proposed that cLD directly binds unfolded proteins, which changes the quaternary association of the monomers in the membrane plane, whichChanges in the ER lumen in turn position Ire1 kinase domains in the cytoplasm optimally for autophosphorylation to initiate the UPR.
Cancer ResearchXBP1 Is Essential for Survival under Hypoxic Conditions and Is Required for Tumor Growth
570 Citations2004Lorenzo Romero‐Ramírez, Hongbin Cao +10 more
These studies directly implicate XBP1 as an essential survival factor for hypoxic stress and tumor growth.
Annual Review of Cell and Developmental BiologyIntracellular Signaling by the Unfolded Protein Response
535 Citations2006Sebastián Bernales, Feroz R. Papa +1 more
Results shed light on the mechanisms by which unfolded proteins are sensed in the ER and by which the unfolded protein signals are relayed and integrated to reestablish homeostasis in the cell's protein folding capacity or-if this cannot be achieved-commit cells to apoptosis.
CellThe Biological and Chemical Basis for Tissue-Selective Amyloid Disease
494 Citations2005Yoshiki Sekijima, R. Luke Wiseman +6 more
It is demonstrated that mammalian cells secrete numerous transthyretin disease-associated variants with wild-type efficiency in spite of compromised folding energetics and proposed that ERAF (influenced by the energetICS of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue.
The EMBO JournalStress‐induced gene expression requires programmed recovery from translational repression
468 Citations2003Isabel Novoa, Yuhong Zhang +4 more
Observations indicate that GADD34 controls a programmed shift from translational repression to stress‐induced gene expression, and reconciles the apparent contradiction between the translational and transcriptional arms of cellular stress responses.
The EMBO JournalXBP‐1 is required for biogenesis of cellular secretory machinery of exocrine glands
448 Citations2005Ann–Hwee Lee, Gerald C. Chu +2 more
It is proposed that XBP‐1 is both necessary and sufficient for the full biogenesis of the secretory machinery in exocrine cells.
Molecular and Cellular BiologyActivating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress
444 Citations2004Jaime D. Blais, Vasilisa Filipenko +6 more
It is shown that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response, and an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.
CelltRNA Ligase Is Required for Regulated mRNA Splicing in the Unfolded Protein Response
441 Citations1996Carmela Sidrauski, Jeffery S. Cox +1 more
The results suggest that the regulated splicing of HAC1 mRNA occurs by a novel pathway, involving tRNA ligase and bypassing the spliceosome.
Journal of Biological ChemistryDelineation of a Negative Feedback Regulatory Loop That Controls Protein Translation during Endoplasmic Reticulum Stress
432 Citations2003Yanjun Ma, Linda M. Hendershot
The essential role of GADD34 in the resumption of protein synthesis is demonstrated, the pathway for its induction is defined, and cytoprotective unfolded protein response targets like BiP are sensitive to the eIF-2α-mediated block in translation are revealed.
Molecular and Cellular BiologyPhosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular Stresses
424 Citations2003Hao-Yuan Jiang, Sheree A. Wek +5 more
It is suggested that eIF2alpha kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIFalpha phosphorylation is central to activation of the NF-kappaB.
Nature MedicineControl of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis
415 Citations2005Donalyn Scheuner, Dirk Vander Mierde +7 more
It is proposed that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.
Molecular Biology of the CellThe unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.
410 Citations1997Jeffery S. Cox, Rowan E. Chapman +1 more
It is demonstrated that the ER-resident proteins by the unfolded protein response and membrane lipid synthesis by the inositol response are intimately linked, forming different branches of the same pathway.
The Journal of Cell BiologypXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response
409 Citations2006Hiderou Yoshida, Masaya Oku +2 more
It is shown that pXBP1 unspliced (U) encoded in XBP1 pre-mRNA was constitutively expressed and markedly accumulated at the recovery phase of ER stress, and is a negative feedback regulator of pX BP1(S), which shuts off the transcription of target genes during the recoveryphase of ER Stress.
The EMBO JournalCytoprotection by pre‐emptive conditional phosphorylation of translation initiation factor 2
388 Citations2004Phoebe D. Lu, Céline Jousse +7 more
The findings indicate that eIF2α phosphorylation can initiate signaling in a cytoprotective gene expression pathway independently of other parallel stress‐induced signals and that activation of this pathway can single‐handedly promote a stress‐resistant preconditioned state.
Eukaryotic CellGcn4p, a Master Regulator of Gene Expression, Is Controlled at Multiple Levels by Diverse Signals of Starvation and Stress
384 Citations2002Alan G. Hinnebusch, Krishnamurthy Natarajan
All cells undergo rapid transcriptional reprogramming in response to environmental changes by mobilizing transcriptional activators and repressors.
Molecular and Cellular BiologyGrowth Arrest and DNA Damage-Inducible Protein GADD34 Targets Protein Phosphatase 1α to the Endoplasmic Reticulum and Promotes Dephosphorylation of the α Subunit of Eukaryotic Translation Initiation Factor 2
379 Citations2003Matthew Brush, Douglas C. Weiser +1 more
It is shown that the expression of human GADD34 in cultured cells reversed eIF-2α phosphorylation induced by thapsigargin and tunicamycin, agents that promote protein unfolding in the endoplasmic reticulum (ER).
Proceedings of the National Academy of SciencesThe crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response
367 Citations2006Jiahai Zhou, Chuan Yin Liu +5 more
Structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling.
Genes to Cells<b>Signalling from endoplasmic reticulum to nucleus: transcription factor with a basic‐leucine zipper motif is required for the unfolded protein‐response pathway</b>
366 Citations1996Kazutoshi Mori, Tetsushi Kawahara +3 more
Accumulation of unfolded proteins in the endoplasmic reticulum triggers the transcriptional induction of molecular chaperones and folding enzymes localized in the ER, which triggers an intracellular signalling pathway from the ER to the nucleus, called the unfolded protein‐response (UPR) pathway.
The EMBO JournalGene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control
364 Citations2006Marianne Koritzinsky, Michaël G. Magagnin +12 more
Qualitative RT–PCR analysis of polysomal RNA indicates that the translation efficiency of individual genes varies widely during hypoxia, and regulates mRNA translation through distinct mechanisms each with important contributions to hypoxic gene expression.
The Journal of Cell BiologyInhibition of a constitutive translation initiation factor 2α phosphatase, <i>CReP</i>, promotes survival of stressed cells
331 Citations2003Céline Jousse, Seiichi Oyadomari +5 more
It is suggested that therapeutic inhibition of eIF2α dephosphorylation by targeting the CReP-protein–phosphatase-1 complex may be used to access the salubrious qualities of the ISR.
CellBlock of HAC1 mRNA Translation by Long-Range Base Pairing Is Released by Cytoplasmic Splicing upon Induction of the Unfolded Protein Response
320 Citations2001Ursula Rüegsegger, Jess H. Leber +1 more
It is shown that the polysomal, cytoplasmic pool of HAC1 mRNA is a substrate for splicing, suggesting that the stalled ribosomes may resume translation after the intron is removed.
Biochemical and Biophysical Research CommunicationsDissociation of Kar2p/BiP from an ER Sensory Molecule, Ire1p, Triggers the Unfolded Protein Response in Yeast
307 Citations2000Katsutomo Okamura, Yukio Kimata +3 more
Yeast ER chaperone Kar2p/BiP, a member of the HSP70 family found in the ER, directly regulates the unfolded protein response by the interaction with Ire1p, similar to the regulation of mammalian cytosolic chaper one Hsp70 via its interaction with heat shock factor 1.
Molecular Biology of the CellDiverse and Specific Gene Expression Responses to Stresses in Cultured Human Cells
301 Citations2004John I. Murray, Michael L. Whitfield +4 more
CDNA microarrays used in a systematic study of the gene expression responses of HeLa cells and primary human lung fibroblasts to heat shock, endoplasmic reticulum stress, oxidative stress, and crowding revealed groups of genes with coherent biological themes, including genes that responded to specific stresses and others that response to multiple types of stress.
Molecular Cancer ResearchThe Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors
296 Citations2005Douglas E. Feldman, Vibha Chauhan +1 more
Although the exact mechanism has yet to be elucidated, recent data suggest that the UPR affects tumor growth through protection from apoptosis and may influence angiogenic signaling pathways.
Molecular and Cellular BiologyPerk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress
287 Citations2006Jaime D. Blais, Christina Addison +9 more
It is suggested that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
CellSubstrate-Specific Translocational Attenuation during ER Stress Defines a Pre-Emptive Quality Control Pathway
283 Citations2006Sang‐Wook Kang, Neena S. Rane +4 more
Protein translocation is a physiologically regulated process that is utilized for pQC as part of the ER stress response and is found that during acute ER stress, translocation of secretory and membrane proteins is rapidly and transiently attenuated in a signal sequence-selective manner.
Journal of NeurochemistryCHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an <i>in vivo</i> neurotoxin model of parkinsonism
283 Citations2005Robert M. Silva, Vincent Ries +11 more
The role of CHOP depends on the nature of the toxic stimulus, and for 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.
Proceedings of the National Academy of SciencesInhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME.
279 Citations1996Colin Jamora, Gunther Dennert +1 more
It is reported that molecular inhibition of GRP78/BiP induction in the fibrosarcoma B/C10ME, while not affecting in vitro cell proliferation, causes a dramatic increase in apoptotic cell death upon Ca2+ depletion of the endoplasmic reticulum.
Journal of Biological ChemistryEnrichment of Endoplasmic Reticulum with Cholesterol Inhibits Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase-2b Activity in Parallel with Increased Order of Membrane Lipids
278 Citations2004Yankun Li, Mingtao Ge +9 more
It is speculated that SERCA2b, a conformationally active protein with 11 membrane-spanning regions, loses function due to decreased conformational freedom in FC-ordered membranes, which may underlie the critical connection between excess cholesterol, unfolded protein response induction, macrophage death, and plaque destabilization in advanced atherosclerosis.
The Journal of Cell BiologyA role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1
275 Citations2004Yukio Kimata, Daisuke Oikawa +3 more
It is concluded that in the ER stress-sensory system BiP is not the principal determinant of Ire1 activity, but an adjustor for sensitivity to various stresses.
Molecular and Cellular BiologyGrowth Arrest and DNA Damage-Inducible Protein GADD34 Assembles a Novel Signaling Complex Containing Protein Phosphatase 1 and Inhibitor 1
272 Citations2001John H. Connor, Douglas C. Weiser +3 more
Modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues and is suggested to be responsible for growth arrest and DNA damage-inducible protein.
Proceedings of the National Academy of SciencesBiP and Sec63p are required for both co- and posttranslational protein translocation into the yeast endoplasmic reticulum.
258 Citations1995Jeffrey L. Brodsky, Jennifer L. Goeckeler-Fried +1 more
Two interacting heat shock cognate proteins in the lumen of the yeast endoplasmic reticulum, Sec63p and Kar2p, are required for posttranslational translocation of yeast alpha-factor precursor in vitro and the import of invertase into wild-type, sec63, and kar2 mutant yeast membranes is examined.
PLoS GeneticsGenetic Interactions Due to Constitutive and Inducible Gene Regulation Mediated by the Unfolded Protein Response in C. elegans
253 Citations2005Xiaohua Shen, Ronald Ellis +2 more
Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR genes that require the ER stress transducers during normal development and identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.
ScienceBypassing a Kinase Activity with an ATP-Competitive Drug
229 Citations2003Feroz R. Papa, Chao Zhang +2 more
The role of Ire1's kinase domain was explored by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1, and a conformational change in the kinasedomain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.
The EMBO JournalATF6 modulates SREBP2‐mediated lipogenesis
214 Citations2004Lingfang Zeng, Min Lü +5 more
It is reported that glucose deprivation activated ATF6 but suppressed the SREBP2‐regulated transcription, and a novel mechanism by which ATF6 antagonizes SRE BP2 to regulate the homeostasis of lipid and glucose is provided.
The Journal of Cell BiologyActivation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK
177 Citations2006Stefan J. Marciniak, Lidia García‐Bonilla +3 more
It is reported that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex, and this switch correlates with a marked change to the protease sensitivity pattern, indicative of a major conformational change in the PERK kinase domain upon activation.
PLoS BiologyGcn4p and Novel Upstream Activating Sequences Regulate Targets of the Unfolded Protein Response
176 Citations2004Christopher K. Patil, Hao Li +1 more
The discovery of a role for Gcn4p in the yeast UPR reveals an additional level of complexity and demonstrates a surprising conservation of the signaling circuit between yeast and metazoan cells.
NeurologyThe effect of genotype on the natural history of eIF2B-related leukodystrophies
166 Citations2004Anne Fogli, Raphael Schiffmann +13 more
The degree of eif2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.
Journal of Biological ChemistryDouble-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis
132 Citations2006Donalyn Scheuner, Rupali Patel +7 more
It is proposed that eIF2α phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events.
Biochemical JournalInhibition of phosphatidylcholine synthesis induces expression of the endoplasmic reticulum stress and apoptosis-related protein CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153)
94 Citations2003Michiel H.M. van der Sanden, Martin Houweling +2 more
The results suggest that PC depletion in MT58 induces the ER-stress-related protein CHOP, without raising a general ER stress response.
PLoS BiologyIRE1-Independent Gain Control of the Unfolded Protein Response
88 Citations2004Jess H. Leber, Sebastián Bernales +1 more
A heretofore unrecognized pathway operates in yeast to regulate the transcription of HAC1, and by adding an additional signaling element to the basic UPR circuit, a simple switch is transformed into a complex response.
Cell MetabolismBioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression
87 Citations2005Heather P. Harding, Yuhong Zhang +7 more
Interestingly, compound-mediated activation of sterol-regulated genes was enhanced in cells with an ISR-blocking mutation in the regulatory phosphorylation site of eIF2alpha, suggesting a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress.
Molecular Biology of the CellStable Ribosome Binding to the Endoplasmic Reticulum Enables Compartment-specific Regulation of mRNA Translation
86 Citations2005Samuel B. Stephens, Rebecca D. Dodd +4 more
It is demonstrated that ribosome release from the ER is termination independent and new and unexpected roles for the ER compartment in the translational response to induction of the unfolded protein response are identified.
Genome biologyGenome-scale approaches for discovering novel nonconventional splicing substrates of the Ire1 nuclease
75 Citations2004Maho Niwa, Christopher K. Patil +2 more
The approach described here, which combines biochemical and genetic 'fractionation' of mRNA with a novel application of cDNA microarrays, is generally applicable to the study of pathways in which RNA metabolism and alternative splicing have a regulatory role.
The Journal of Cell BiologyRegulation of Antioxidant Metabolism by Translation Initiation Factor 2α
67 Citations2001Shirlee Tan, Nikunj V. Somia +2 more
EIF2α is a critical regulatory factor in the response of nerve cells to oxidative stress and in the control of the major intracellular antioxidant, GSH, and may play a central role in the many neurodegenerative diseases associated with oxidative stress.
…