Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6alpha, and ATF6beta to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58(IPK), ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6alpha induced a subset of UPR target genes, cells deficient in ATF6alpha, ATF6beta, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6alpha had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6alpha may serve partially redundant functions. No UPR target genes that required ATF6beta were identified, nor, in contrast to XBP-1 and ATF6alpha, did the activity of the UPRE or ERSE promoters require ATF6beta, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.
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PMID:XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. 1455 94

Accumulation of misfolded proteins within the lumen of the mammalian endoplasmic reticulum (ER) activates the unfolded protein response (UPR). ATF6 and Ire1p are ER-associated proteins that control UPR-specific transcription systems in mammals; UPR signaling involves cleavage of ATF6 and splicing of XBP1 mRNA initiated by Ire1p. We tested the hypothesis that activation of ATF6 and/or Ire1p determines the levels of mRNAs derived from target genes encoding GRP78/BiP and EDEM. By subjecting dermal fibroblasts to multiple stresses, strong correlations were found between ATF6 activation and XBP1 splicing, and between GRP78/BiP mRNA and EDEM mRNA accumulation. Surprisingly, there was no reasonable correlation between activation of either signal transducer with accumulation of either target transcript. Thus, ATF6 and Ire1p signaling do not define the magnitude of UPR-dependent mRNA increases, even though they may be necessary for gene activation, suggesting the existence of additional stress-sensitive factors acting as "coincidence detectors" for transcript accumulation.
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PMID:Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts. 1506 70

To determine whether oscillations of cytoplasmic [Ca(2+)] might be involved in transcription regulated by the unfolded protein response (UPR), dermal fibroblasts were loaded with the widely used Ca(2+) buffer BAPTA, which is expected to dampen cytoplasmic [Ca(2+)] changes without affecting resting [Ca(2+)]. BAPTA inhibited UPR-dependent transcription of the GRP78/BiP and EDEM genes. However, BAPTA also blocked cytoplasmic stress-dependent (UPR-independent) transcription of the HSP70 gene. These results led to the unexpected demonstration that BAPTA was a general inhibitor of cellular RNA synthesis in dermal fibroblasts. BAPTA is delivered to the cytoplasm as the acetoxymethyl (AM) ester BAPTA/AM, but released AM groups, as well as formaldehyde generated from AM breakdown, were ruled out as causes of RNA synthesis inhibition. BAPTA inhibited RNA synthesis in all mammalian cell types tested except CHO-K1. GRP78/BiP RNA induction in CHO-K1 cells was not blocked by BAPTA. Thus, there does not appear to be a critical requirement for cytoplasmic [Ca(2+)] changes in CHO-K1 UPR-dependent transcription. However, general inhibition of RNA synthesis by the [Ca(2+)] buffer BAPTA was unanticipated. This might possibly reflect a fortuitous interaction of BAPTA with the RNA synthesis machinery or a requirement for [Ca(2+)] changes.
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PMID:Inhibition of mammalian RNA synthesis by the cytoplasmic Ca2+ buffer BAPTA. Analyses of [3H]uridine incorporation and stress-dependent transcription. 1526 May 1

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response. IRE1, PERK, ATF6, BiP, EDEM, lipid-linked oligosaccharides (LLOs), and XBP1 directly or indirectly participate in this process. This article provides methods used in our laboratory to quantitatively measure the accumulation of mRNAs encoding BiP and EDEM; splicing of XBP-1; cleavage of ATF6; inhibition of protein synthesis by PERK; and extension of LLOs under control and stress conditions.
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PMID:Quantitative measurement of events in the mammalian unfolded protein response. 1580 12

Injury due to cold ischaemia-reperfusion (IR) represents a major cause of primary graft non-function following human liver transplantation. This major cellular response translates into a dramatic decrease in intracellular ATP concentration during the ischaemic phase, thus sensitizing cells to reperfusion shock. We postulated that IR-induced cellular damage might cause alterations of the secretory pathway, particularly at the level of endoplasmic reticulum (ER) function. Under these circumstances, the ER triggers an adaptive response named the 'unfolded protein response' (UPR). In this study, we show that the expression of BiP, CHOP/GADD153 and GADD34, known to be induced specifically upon ER stress, are differentially affected upon IR, thus suggesting that distinct ER stress responses are activated during each phase of transplantation. With an approach combining semi-quantitative RT-PCR and immunoblotting using phospho-specific antibodies, we show that the IRE-1 pathway is activated upon early ischaemia and, in a second phase, upon early reperfusion. This occurs through the atypical splicing of XBP-1 mRNA, its translation into a transcriptionally active XBP-1 protein and the subsequent increase in EDEM mRNA expression, and may also contribute to the observed reperfusion-induced activation of MAPK/SAPK. In contrast, we demonstrate that the PERK pathway, leading to inhibition of cap-dependent translation, is mainly activated upon reperfusion, as shown by PERK and eIF2alpha phosphorylation. PERK activation is detected restrictively in sinusoidal endothelial cells and could contribute to the exaggerated sensivity of this liver cell type to IR injury. These results correlate well with the observed defect in protein secretion and suggest that the biphasic ER stress response may influence liver secretory functions and, as a consequence, condition liver transplantation outcomes.
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PMID:Distinct endoplasmic reticulum stress responses are triggered during human liver transplantation. 1591 76

The field of endoplasmic reticulum (ER) stress in mammalian cells has expanded rapidly during the past decade, contributing to understanding of the molecular pathways that allow cells to adapt to perturbations in ER homeostasis. One major mechanism is mediated by molecular ER chaperones which are critical not only for quality control of proteins processed in the ER, but also for regulation of ER signaling in response to ER stress. Here, we summarized the properties and functions of GRP78/BiP, GRP94/gp96, GRP170/ORP150, GRP58/ERp57, PDI, ERp72, calnexin, calreticulin, EDEM, Herp and co-chaperones SIL1 and P58(IPK) and their role in development and diseases. Many of the new insights are derived from recently constructed mouse models where the genes encoding the chaperones are genetically altered, providing invaluable tools for examining the physiological involvement of the ER chaperones in vivo.
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PMID:ER chaperones in mammalian development and human diseases. 1748 12

Membrane and secretory proteins cotranslationally enter and are folded in the endoplasmic reticulum (ER). Misfolded or unassembled proteins are discarded by a process known as ER-associated degradation (ERAD), which involves their retrotranslocation into the cytosol. ERAD substrates frequently contain disulfide bonds that must be cleaved before their retrotranslocation. Here, we found that an ER-resident protein ERdj5 had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ERAD through its physical and functional associations with EDEM (ER degradation-enhancing alpha-mannosidase-like protein) and an ER-resident chaperone BiP. Thus, ERdj5 is a member of a supramolecular ERAD complex that recognizes and unfolds misfolded proteins for their efficient retrotranslocation.
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PMID:ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. 1865 71

Down-regulation of the unfolded protein response (UPR) can be therapeutically valuable in cancer treatment, and endoplasmic reticulum (ER)-resident chaperone proteins may thus be targets for developing novel chemotherapeutic strategies. ERdj5 is a novel ER chaperone that regulates the ER-associated degradation of misfolded proteins through its associations with EDEM and the ER stress sensor BiP. To investigate whether ERdj5 can regulate ER stress signaling pathways, we exposed neuroblastoma cells overexpressing ERdj5 to ER stress inducers. ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells. To provide further evidence that ERdj5 induces ER stress-regulated apoptosis, we targeted Bcl-2 to ER of ERdj5-overexpressing cells. Targeting the Bcl-2 to ER prevented the apoptosis induced by ER stress inducers but not by non-ER stress apoptotic stimuli, suggesting induction of ER stress-regulated apoptosis by ERdj5. ERdj5 enhanced apoptosis by abolishing the ER stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and the subsequent translational repression. ERdj5 was found to inhibit the eIF2alpha phosphorylation under ER stress through inactivating the pancreatic endoplasmic reticulum kinase. The compromised integrated stress response observed in ERdj5-overexpressing ER-stressed cells due to repressed eIF2alpha phosphorylation correlated with impaired neuroblastoma cell resistance under ER stress. These results demonstrate that ERdj5 decreases neuroblastoma cell survival by down-regulating the UPR, raising the possibility that this protein could be a target for anti-tumor approaches.
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PMID:ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis. 1912 39

Picornavirus infection alters the endoplasmic reticulum (ER) membrane but it is unclear whether this induces ER stress. Infection of rhabdomyosarcoma cells with enterovirus 71 (EV71), a picornavirus, caused overexpression of the ER-resident chaperone proteins, BiP and calreticulin, and phosphorylation of eIF2alpha, but infection with UV-inactivated virus did not, indicating that ER stress was induced by viral replication and not by viral attachment or entry. Silencing (si)RNA knockdown demonstrated that phosphorylation of eIF2alpha was dependent on PKR: eIF2alpha phosphorylation was reduced by siPKR but not by siPERK. We provided evidence showing that PERK is upstream of PKR and is thus able to negatively regulate the PKR-eIF2alpha pathway. Pulse-chase experiments revealed that EV71 infection inhibited translation and activation of ATF6. Expression of BiP at the protein level was activated by a virus-dependent, ATF6-independent mechanism. EV71 upregulated XBP1 mRNA level, but neither IRE1-mediated XBP1 splicing nor its active spliced protein was detected, and its downstream gene, EDEM, was not activated. Epigenetic BiP overexpression alleviated EV71-induced ER stress and reduced viral protein expression and replication. Our results suggest that EV71 infection induces ER stress but modifies the outcome to assist viral replication.
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PMID:Endoplasmic reticulum stress is induced and modulated by enterovirus 71. 2007 Mar 7

The mechanism, in molecular terms of protein quality control, specifically of how the cell recognizes and discriminates misfolded proteins, remains a challenge. In the secretory pathway the folding status of glycoproteins passing through the endoplasmic reticulum is marked by the composition of the N-glycan. The different glycoforms are recognized by specialized lectins. The folding sensor UGGT acts as an unusual molecular chaperone and covalently modifies the Man9 N-glycan of a misfolded protein by adding a glucose moiety and converts it to Glc1Man9 that rebinds the lectin calnexin. However, further links between the folding status of a glycoprotein and the composition of the N-glycan are unclear. There is little unequivocal evidence for other proteins in the ER recognizing the N-glycan and also acting as molecular chaperones. Nevertheless, based upon a few examples, we suggest that this function is carried out by individual proteins in several different complexes. Thus, calnexin binds the protein disulfide isomerase ERp57, that acts upon Glc1Man9 glycoproteins. In another example the protein disulfide isomerase ERdj5 binds specifically to EDEM (which is probably a mannosidase) and a lectin OS9, and reduces the disulfide bonds of bound glycoproteins destined for ERAD. Thus the glycan recognition is performed by a lectin and the chaperone function performed by a specific partner protein that can recognize misfolded proteins. We predict that this will be a common arrangement of proteins in the ER and that members of protein foldase families such as PDI and PPI will bind specifically to lectins in the ER. Molecular chaperones BiP and GRp94 will assist in the folding of proteins bound in these complexes as well as in the folding of non-glycoproteins.
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PMID:Protein quality control in the ER: the recognition of misfolded proteins. 2034 46


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