casSAR Dugability of Q96DN0 | ERP27 | Endoplasmic reticulum resident protein 27 - Also known as ERP27_HUMAN, ERP27, C12orf46. Specifically binds unfolded proteins and may recruit protein disulfide isomerase PDIA3 to unfolded substrates (PubMed:16940051, PubMed:23192347). Binds protein substrates via a hydrophobic pocket in the C-terminal domain (PubMed:16940051, PubMed:23192347). May play a role in the unfolded stress response (PubMed:23192347). Interacts with PDIA3.
Implementation of dendritic cell- (DC-) based therapies in organ transplantation can reduce dependency on nonspecific immunosuppression. Despite extensive research, mechanisms of equipped DCs inducing transplant tolerance remain incomplete. Here, we applied RNA interference technique to inhibit CD80 and CD86 expression in host bone marrow-derived DCs. This approach could specifically and effectively knock down CD80 and CD86 expression. T cells primed by these DCs inhibited allogeneic responses. Administration of recipient DCs loaded with alloantigen after CD80 and CD86 blockade prolonged cardiac allograft survival. We also found a higher percentage of apoptotic T cells in lymph tissues and grafts than that detected in control group. In addition, these T cells expressed high expression of GRP78 than controls, indicating activation of unfolded protein responses. Upregulation of CHOP expression among these cells suggested that the endoplasmic reticulum stress (ERS) response switched to a proapoptotic
Title: Mif1: A Missing Link between the Unfolded Protein Response Pathway and ER-Associated Protein Degradation?. VOLUME: 2 ISSUE: 2. Author(s):Theo van Laar, Alex J. van der Eb and Carrol Terleth. Affiliation:MGC-Department ofRadiation Genetics and Chemical Mutagenesis, Leiden University MedicalCenter, P. O. Box 9503, 2300 RA Leiden, the Netherlands. Keywords:Eukaryotic cells, ER-Associated Protein Degradation, Alzheimers disease, protein disulfide isomerase (PDI), ER-lumenal part, UPR-independent functions, multi-membrane spanning ER, RING-domain, E3 Ubiquitin Ligase, ER-stress. Abstract: Eukaryotic cells have three different mechanisms to deal with the accumulation of unfolded proteins in the endoplasmic reticulum: (1) In cells in which unfolded polypeptides accumulate, translation initiation is inhibited to prevent further accumulation of unfolded proteins. (2) Expression of proteins involved in polypeptide folding is strongly enhanced by a process called the Unfolded Protein Response (UPR). ...
ER retention refers to proteins that are retained in the endoplasmic reticulum, or ER, after folding; these are known as ER resident proteins. Their localization to the ER often depends on certain sequences of amino acids located at the N-terminus or C-terminus. The classical ER retention signal is the C-terminal KDEL sequence for lumen bound proteins and KKXX for transmembrane localization. These signals allow for retrieval from the Golgi apparatus by ER retention receptors, effectively maintaining the protein in the ER.[1] Other mechanisms for ER retention are being studied but are not as well characterized as signal retention. ...
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Fig. 4. Hrd1p/Hrd3p cross-linking to Hmg2p did not require the presence of Ubc7p or Cue1p. (a) Hrd3p cross-linking to Hmg2p in the presence of either the hrd1Δ, ubc7Δ, orcue1Δ allele. The appropriate null alleles of each gene required for Hmg2p degradation were introduced into the strain coexpressing 1myc-Hmg2p and 3HA-Hrd3p. Cross-linking assay was performed as in Fig. 1. (b) Hrd1p cross-linking to Hmg2p in the presence of either the hrd1Δ, ubc7Δ, orcue1Δ allele. The appropriate null alleles of each gene required for Hmg2p degradation were introduced into the strain coexpressing 1myc-Hmg2p and 3HA-Hrd1p, and the cross-linking assay was performed. (c) Hrd3p function was required for Hrd1p cross-linking to Hmg2p under normal Hrd1p expression levels. Cells expressing 1myc-Hmg2p and 3HA-Hrd1p from its native promoter and coexpressing either the wild-type HRD3 allele (wt), the hrd3Δ allele, or the truncated hrd3 allele (hrd3357-833 ) were subjected to the cross-linking assay. (d) Expression ...
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I endoplasmic reticulum transmembrane protein containing a stress-sensing domain facing the endoplasmic reticulum lumen and a cytosolic kinase domain. PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. PERK regulates proliferation of beta cells during embryonic and neonatal development and is essential for viability of acinar cells in mouse exocrine pancreas, neither of which is associated with endoplasmic reticulum stress response. PERK is also required for endoplasmic reticulum functions including proinsulin trafficking and quality control in beta cells. Similarly, PERK modulates proliferation and differentiation of osteoblasts as well as secretion of type I collagen. PERK phosphorylates α subunit of the translation ...
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Oxidative Medicine and Cellular Longevity is a unique peer-reviewed, Open Access journal that publishes original research and review articles dealing with the cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, metabolism, cellular survival and cellular longevity. Oxidative stress impacts almost all acute and chronic progressive disorders and on a cellular basis is intimately linked to aging, cardiovascular disease, cancer, immune function, metabolism and neurodegeneration. The journal fills a significant void in todays scientific literature and serves as an international forum for the scientific community worldwide to translate pioneering
Probable lectin that binds selectively to improperly folded lumenal proteins. May function in endoplasmic reticulum quality control and endoplasmic reticulum-associated degradation (ERAD) of both non-glycosylated proteins and glycoproteins.
In a previous study we reported the presence of a large conductance K+ channel in the membrane of endoplasmic reticulum (ER) from rat hepatocytes. The channel open probability (Po) appeared voltage dependent and reached to a minimum 0.2 at +50 mV. Channel activity in this case was found to be totally inhibited at ATP concentration 2.5 mM, glibenclamide 100 μM and tolbutamide 400 μM. Existing evidence indicates an impairment of endoplasmic reticulum functions in ER stress condition. Because ER potassium channels have been involved in several ER functions including cytoprotection, apoptosis and calcium homeostasis, a study was carried out to consider whether the ER potassium channel function is altered in a high fat diet model of ER stress. Male Wistar rats were made ER stress for 2 weeks with a high fat diet. Ion channel incorporation of ER stress model into the bilayer lipid membrane allowed the characterization of K+ channel. Our results indicate that the channel Po was significantly ...
ENCODES a protein that exhibits enzyme binding (ortholog); ubiquitin conjugating enzyme binding (ortholog); ubiquitin protein ligase activity (ortholog); INVOLVED IN proteasomal protein catabolic process (ortholog); proteasome-mediated ubiquitin-dependent protein catabolic process (ortholog); protein K48-linked ubiquitination (ortholog); PARTICIPATES IN Endoplasmic Reticulum-associated degradation pathway; ASSOCIATED WITH familial adult myoclonic epilepsy 3 (ortholog); FOUND IN endoplasmic reticulum (ortholog); integral component of endoplasmic reticulum membrane (ortholog); integral component of membrane (ortholog); INTERACTS WITH bis(2-ethylhexyl) phthalate; chromium(6+); ethanol
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Prevents formation of cytosolic aggregates of unfolded glycoproteins that have been retrotranslocated into the cytosol. Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type (By similarity).
Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic
The biogenesis of nascent proteins translocated into the calcium‐rich, oxidizing milieu of the endoplasmic reticulum (ER) lumen is assisted by a group of resident ER proteins that include molecular chaperones and folding enzymes. These specialized ER proteins are constitutively expressed in all cells, where they play a role in monitoring and assisting the maturation of normal proteins (Gething and Sambrook, 1992; Hendrick and Hartl, 1993) and are essential for proper steady‐state operations of the eukaryotic secretory pathway. Expression of mutant secretory pathway proteins or exposure of cells to agents that adversely affect ER protein folding and maturation all result in the accumulation of unfolded proteins in the ER, thereby activating an inter‐organelle signaling pathway linking the ER and nucleus. This response, termed the unfolded protein response (UPR), includes the coordinate transcriptional up‐regulation of ER chaperones and folding enzymes (Lee, 1992).. In yeast, an ER ...
There are many contact sites of ER-PM in different cell types. The function of ER-plasma membrane contact sites is similar to that of the mitochondria-ER junctions, since Ca2+ homeostasis and lipid synthesis and trafficking take place there. As mentioned above, Ca2+ regulation is crucial as it is also responsible for protein synthesis, folding, and signaling. In excitable cells, the global calcium signal is generated by the coupling of PM depolarization and ER calcium release. In non-excitable cells, calcium influx is controlled by detecting luminal ER Ca2+ levels. Research has showed that the PM-ER contact site is involved in non-vesicular lipid trafficking. We know that lipids are insoluble in water. So to transfer lipid from its synthesis sites to its desired work place, one must shield the lipid. In fact, couple families of lipid transfer protein (LTPs) that can perform this task have been found on the contact sites. One of them is oxysterol-binding protein (OSBP) related proteins(ORPS). The ...
Plant cells, like cells from other kingdoms, have the ability to self-destruct in a genetically controlled manner. This process is defined as Programmed Cell Death (PCD). PCD can be triggered by various stimuli in plants including by endoplasmic reticulum (ER) stress. Research in the past two decades discovered that disruption of protein homeostasis in the endoplasmic reticulum (ER) could cause ER stress, which when prolonged/unresolved leads cells into PCD. ER stress-induced PCD is part of several plant processes, for instance, drought and heat stress have been found to elicit ER stress-induced PCD. Despite the importance of ER stress-induced PCD in plants, its regulation remains largely unknown, when compared with its counterpart in animal cells. In mammalian cells, several pro-apoptotic proteases called caspases were found to play a crucial role in ER stress-induced PCD. Over the past decade, several key proteases with caspase-like enzymatic activity have been discovered in plants and implicated in
The endoplasmic reticulum is a major organelle in all eukaryotic cells which performs multiple functions including protein and lipid synthesis and sorting, drug metabolism, and Ca 2+ storage and release. The endoplasmic reticulum, and its specialized muscle counterpart the sarcoplasmic reticulum, is the largest and most extensive of Ca 2+ storage organelle in eukaryotic cells, often occupying in excess of 10% of the cell volume. There are three major components of Ca 2+ storage organelles which mediate their major functions: Ca 2+ uptake, mediated by pumps and exchangers; storage enhanced by luminal Ca 2+ binding proteins, and Ca 2+ mobilization mediated by specific ion channels. Ca 2+ mobilization from the endoplasmic reticulum plays a central role in Ca 2+ signaling. Through Ca 2+ release channels in its membrane, the pervading and plastic structure of the endoplasmic reticulum allows Ca 2+ release to be rapidly targeted to specific cytoplasmic sites across the whole cell. That several
Communication between organelles is essential to coordinate cellular functions and the cells response to physiological and pathological stimuli. Organellar communication occurs at membrane contact sites (MCSs), where the endoplasmic reticulum (ER) membrane is tethered to cellular organelle membranes by specific tether proteins and where lipid transfer proteins and cell signaling proteins are located. MCSs have many cellular functions and are the sites of lipid and ion transfer between organelles and generation of second messengers. This review discusses several aspects of MCSs in the context of lipid transfer, formation of lipid domains, generation of Ca2+ and cAMP second messengers, and regulation of ion transporters by lipids. ...
A summary of the article is shown below:. Purpose: The aim of the study was to examine the effects of resveratrol upon hepatic endoplasmic reticulum stress (ERS) and insulin sensitivity in vivo and in vitro. Material and methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks, and insulin resistance was evaluated by the intraperitoneal glucose tolerance test (IPGTT). Mice were then treated with resveratrol for 12 weeks and blood and liver samples collected. Blood biochemical indicators were determined by kits, liver protein expression was determined by western blot, and morphological changes were observed by histological staining. Palmitic acid (PA)-induced insulin-resistant HepG2 cells were established. Cells were exposed to 100, 50 or 20 μM resveratrol for 24 hrs, and proliferation/cytotoxicity was determined. Cells were divided into five groups: control, PA, PA + Rev (100 μM), PA + Rev (50 μM) and PA + Rev (20 μM) groups. After 24 hrs of treatment, cellular proteins were ...
Engagement of the TNF receptor family of death receptors, including TNF-R1, Fas, Trail-R1, and Trail-R2, with their cognate ligands leads to the recruitment and autoactivation of initiator procaspase-8 (Krammer, 2000). Recent studies implicate that caspase-8 substrates located at distinct cellular loci play key roles in mediating death receptor-induced apoptosis. For example, caspase-8 cleavage of the BH3-only molecule BID promotes mitochondrial release of cyt.c and Smac/Diablo (Yin et al., 1999; Li et al., 2002); cleavage of RIP prevents the activation of NF-κB survival responses (Lin et al., 1999); and cleavage of the cytolinker plectin is important for disassembly of microfilaments (Stegh et al., 2000). In this work, we investigated the consequence of caspase-8 cleavage of BAP31 at the ER by expressing the pro-apoptotic p20 cleavage fragment in cells using an adenovirus vector. This approach allowed us to isolate and delineate a predicted branch of the death receptor signaling cascade. ...
TY - JOUR. T1 - Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells. AU - Lee, Eun Sang. AU - Lee, Hae June. AU - Lee, Yoon Jin. AU - Jeong, Jae Hoon. AU - Kang, Seong Man. AU - Lim, Young Bin. PY - 2014/7/25. Y1 - 2014/7/25. N2 - Radiotherapy, which is one of the most effective approaches to the treatment of various cancers, plays an important role in malignant cell eradication in the pelvic area and abdomen. However, it also generates some degree of intestinal injury. Apoptosis in the intestinal epithelium is the primary pathological factor that initiates radiation-induced intestinal injury, but the mechanism by which ionizing radiation (IR) induces apoptosis in the intestinal epithelium is not clearly understood. Recently, IR has been shown to induce endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) signaling pathway in intestinal epithelial cells. However, the consequences of the IR-induced ...
Ca2+ ions are important second messengers in many cellular signal transduction pathways. Compromised Ca2+ homeostasis and signaling have been linked to many human diseases, including muscle dysfunction and heart failure.1-5 Two principal sources provide Ca2+ to the cell: channels in the plasma membrane (PM) that allow external Ca2+ to enter the cell and internal stores sequestered in the endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR) that release Ca2+. Junctional membrane complexes between PM and ER/SR are present in all excitable cells, providing effective mechanisms for cross-talk between Ca2+ channels/transporters in the PM and Ca2+ release channels in intracellular membranes.6-10 A central focus in cardiovascular research is to understand the basic mechanisms that underlie the control of Ca2+ signaling in the heart and to search for ways to correct the defective Ca2+ signaling process associated with arrhythmogenesis and heart failure.. In the heart, entry of extracellular Ca2+ ...
We have used proteolysis to examine the environment through which nascent secretory proteins are translocated across the membrane of the endoplasmic reticulum. After solubilization of rough microsomes with detergent, fragments comprised of the approximately 70 carboxyl-terminal amino acids of translocating nascent chains initiated and targeted in vivo were protected from digestion by added proteases. About 40 amino acids of nascent chains were protected from proteolysis by the ribosome; thus, membrane-derived components protect an additional 30 amino acids. Under conditions in which those 30 additional amino acids are protected, only a small set of integral membrane proteins remained associated with the ribosome. These proteins include the Sec61 complex previously identified as the core component of the membrane-bound protein translocation apparatus. These results support the concept of a translocation pore that makes intimate contact with the ribosome and thereby protects nascent chains from ...
The endoplasmic reticulum (ER) is a subcellular organelle where proteins are folded with the help of lumenal chaperones. Newly synthesized peptides enter the ER via the sec61 pore and are glycosylated. Correctly folded proteins are packaged into transport vesicles that shuttle them to the Golgi complex. Misfolded proteins are retained within the ER lumen in complex with molecular chaperones. Proteins that are terminally misfolded bind to BiP and are directed toward degradation through the proteasome in a process called ER-associated degradation (ERAD). Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). In certain severe situations, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis ...
ATF6, a membrane-anchored transcription factor from the endoplasmic reticulum (ER) that modulates the cellular response to stress as an effector of the unfolded-protein response (UPR), is a key player in the development of tumors of different origin. reticulum (ER) can be particularly affected by the presence of mutations in secretory proteins or by dynamic changes in the cellular microenvironment, events which are often encountered in cancers. In the ER, these events are sensed by specific sensors, which in turn trigger select Rabbit Polyclonal to CPB2 signaling pathways, collectively named the unfolded-protein response (UPR) (1). The UPR is an adaptive response that allows the cells to either overcome the stress or promote cell death in the case of overwhelming burden (1). Three ER-resident proteins, namely, the protein kinase PKR-like ER kinase (PERK), the inositol-requiring protein 1 alpha (IRE1), and the activating transcription factor 6 alpha (ATF6), have been identified as the major ...
Being a major factory for protein synthesis, assembly, and export, the endoplasmic reticulum (ER) has a precise and robust ER quality control (ERQC) system monitoring its product line. However, when organisms are subjected to environmental stress, whether biotic or abiotic, the levels of misfolded proteins may overwhelm the ERQC system, tilting the balance between the capacity of and demand for ER quality control and resulting in a scenario termed ER stress. Intense or prolonged ER stress may cause damage to the ER as well as to other organelles, or even lead to cell death in extreme cases. To avoid such serious consequences, cells activate self-rescue programs to restore protein homeostasis in the ER, either through the enhancement of protein-folding and degradation competence or by alleviating the demands for such reactions. These are collectively called the unfolded protein response (UPR). Long investigated in mammalian cells and yeasts, the UPR is also of great interest to plant scientists. Among
The endoplasmic reticulum (ER) is an intracellular organelle for protein folding, lipid synthesis and Ca²⁺ storage. It is also responsible for the transportation for most of the secretory and transmembrane proteins. When the protein load exceeds the ER folding capacity, the ER undergoes stress and activates a set of signaling cascades that is termed the unfolded protein response (UPR). The multifunctional GRP78 is the major ER molecular chaperone with protein folding abilities and the master regulator of the UPR, and recently has been shown that a subfraction of it is localized on the cell surface acting as a co-receptor for various signaling pathway activation. ❧ Traditionally GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors, thus, its role in the development of hematologic malignancies remains to be determined. In this thesis, elevated GRP78 expression was detected in leukemic blasts of adult patients, leukemia cell ...
Diabetes is intimately associated with cardiovascular complications. Much evidence highlighted the complex interplay between Endoplasmic Reticulum (ER) stress and oxidative stress in the pathogenesis of diabetes. Hemeoxygenase-1 (HO-1) induction was shown to protect against oxidative stress in diabetes; however the underlying molecular mechanisms have not yet been fully elucidated. We aim in this project to test the hypothesis that HO-1 induction will protect against high glucose-mediated ER stress and oxidative stress in endothelial cells and will enhance cell survival. Endothelial cells were cultured in physiological or high concentrations of glucose in the presence of cobalt protoporphyrin 1X (CoPP, HO-1 inducer), 4-phenylbutyrate (PBA, chemical chaperone to inhibit ER stress) or vehicle. Then, ER stress response was assessed (PCR, western blot). The productions of ROS (flow cytometer) and NO (Griess assay) were analysed. Also, apoptosis and caspase 3/7 activity were assessed. High glucose treatment
Protein targeting to the endoplasmic reticulum can be either co- or posttranslational and involves the binding of a hydrophobic signal sequence by delivery factors such as signal recognition particle or components of the TRC/GET pathway, respectively (1). Inefficient recognition and/or delivery of precursor proteins destined for the endoplasmic reticulum can lead to their cytosolic accumulation, resulting in toxicity such as that observed in neurodegenerative disorders such as prionopathies (2, 3). The disposal of such mislocalized proteins in mammalian cells has recently been shown to depend on the BAG6 complex comprised of the BAG6 protein together with TRC35 and UBL4A. The BAG6 complex recognizes mislocalized proteins, recruits the E2 conjugating enzyme, UbcH5, and an unidentified E3 ligase(s), and thereby selectively promotes the rapid ubiquitination and proteasomal degradation of these substrates (4). This role for the BAG6 complex in cytosolic quality control extends other studies showing ...
The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single, disseminated cancer cells (DCCs) lacking expression of cytokeratin-19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs that were CK19(-) and MHCI(-) The DCCs exhibited an endoplasmic reticulum (ER) stress response but, paradoxically lacked both inositol-requiring enzyme 1alpha activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell-depletion, stimulated the outgrowth of macro-metastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent ...
The biogenesis of most membrane proteins is governed by specific interactions between the newly synthetized nascent polypeptide chain and the evolutionary conserved and essential insertases and translocases (1-3). Insertases and translocases recognize their substrate and lower the free-energy barrier for inserting and folding the polypeptide into cellular membranes (3, 4). This insertion and folding can occur cotranslationally as the polypeptide exits the ribosome or posttranslationally after the polypeptide has been released by the ribosome. The bacterial translocase SecYEG has a eukaryotic homolog, Sec61, in the endoplasmatic reticulum (1), whereas the bacterial insertase YidC has Oxa1 and Oxa2 homologs in mitochondria, Get1 in endoplasmatic reticulum, and Alb3 in chloroplasts (5-7). In Gram-negative bacteria, SecYEG folds α-helical membrane proteins into the inner membrane and translocates precursors of soluble periplasmic and β-barrel outer membrane proteins to the periplasm (1, 8). ...
The endoplasmic reticulum (ER) is an intracellular organelle for protein folding, lipid synthesis and Ca2+ storage. It also is responsible for transporting most secreted and transmembrane proteins to their proper cellular locations. ER undergoes stress when the protein load exceeds its folding capacity, and cellular signaling cascades are activated as unfolded protein response (UPR). GRP78 is a major chaperone assisting protein folding, as well as a master regulator of UPR signaling. In this thesis, we discovered that heterozygosity of Grp78 enhances energy expenditure through upregulation of mitochondria activity, and alleviate high fat diet (HFD)-induced obesity and type 2 diabetes in mouse. The latter is also achieved through increase in insulin sensitivity in the white adipose tissue (WAT) of HFD-fed Grp78+/- mice, with adaptive UPR improving ER folding capacity and quality control. This mechanism is validated through overexpression of the active form of ATF6, a transcription factor known to ...
Hypoxia is an important factor that contributes to tumour aggressiveness and correlates with poor prognosis and resistance to conventional therapy. Therefore, identifying hypoxic environments within tumours is extremely useful for understanding cancer biology and developing novel therapeutic strategies. Several studies have suggested that carbonic anhydrase 9 (CA9) is a reliable biomarker of hypoxia and a potential therapeutic target, while pimonidazole has been identified as an exogenous hypoxia marker. However, other studies have suggested that CA9 expression is not directly induced by hypoxia and it is not expressed in all types of tumours. Thus, in this study, we focused on endoplasmic reticulum disulphide oxidase 1α (ERO1α), a protein that localises in the endoplasmic reticulum and is involved in the formation of disulphide bonds in proteins, to determine whether it could serve as a potential tumour-hypoxia biomarker. Using quantitative real-time polymerase chain reaction, we analysed the mRNA
Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor-independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress-inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, ...
Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the ...
What Additional Protective Layer Of Protein Surrounds Some Viruses - The capsid and envelope play many roles in viral contamination, inclusive of virus attachment to cells, entry into cells, release of the capsid contents into the cells, and packaging of newly fashioned viral debris. The capsid and envelope are also answerable for transfer of the viral genetic material from one mobile to another. these systems also decide the stableness traits of the virus particle, which includes resistance to chemical or bodily inactivation.. The primary role of capsid is to bundle the viral genome. There are strategies related to this feature: the recruitment of the viral RNA all through assembly and the discharge of the genome at some stage in infection. even though particle assembly takes vicinity on endoplasmic reticulum membranes, capsid localizes in nucleoli and lipid droplets.. Because the capsid is outermost, most agents of inactivation must act on the capsid before they can reach the viral RNA, and in ...
1DL2: Crystal structure of a class I alpha1,2-mannosidase involved in N-glycan processing and endoplasmic reticulum quality control.
Accumulation of malfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) and the upregulation of the ER molecular chaperones GRP78 and GRP 94 (1,2). These proteins are normally bound to ER transmembrane proteins such as IRE1p and ATF6 (3,4) but ER stress causes their dissociation. This allows IRE1p, a serine-threonine protein kinase to transduce the unfolded protein signal from the ER to the nucleus. IRE1p also has an endoribonuclease activity that is required to splice X-box binding protein (XBP1) mRNA converting it to a potent UPR transcriptional activation (5). Depletion of IRE1p through the expression of a dominant negative form of IRE1p has no effect on transfected cells, but cell death via apoptosis occurs under stress conditions that cause unfolded proteins to accumulate in the ER (6). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. ...
In dairy cows, the periparturient phase is a stressful period, which is commonly associated with strong metabolic adaptations and the development of pathophysiologic conditions and disorders. Some of the symptoms occurring in the liver, such as the development of fatty liver, are similar to those observed under the condition of endoplasmic reticulum (ER) stress. Therefore, we hypothesized, that in the liver of dairy cows ER stress is induced during the periparturient phase, which in turn leads to an induction of the unfolded protein response (UPR). In order to investigate this hypothesis, we determined relative mRNA concentrations of 14 genes of the ER stress-induced UPR in liver biopsy samples of 13 dairy cows at 3 wk antepartum and 1, 5 and 14 wk postpartum. We found, that the mRNA concentrations of 13 out of the 14 genes involved in the UPR in the liver were significantly increased (1.9 to 4.0 fold) at 1 wk postpartum compared to 3 wk antepartum. From 1 wk postpartum to later lactation, mRNA
Studies with recombinant receptors in cell lines and cultured neurons have defined rules for the trafficking of kainate receptors to the plasma membrane. The relative level of their surface expression depends on subunits and alternative splicing of their C-terminal domain, and on subunit composition of heteromeric receptors. Some subunit splice variants are endowed with a forward trafficking motif, whereas others are retained in the ER (endoplasmic reticulum) due to retention signals.. KA2 was initially thought to require the presence of other subunits to form receptor complexes, but KA2 can in fact form homomeric assemblies in heterologous cells, although it is retained in the ER in the absence of GluR5, GluR6 or GluR7 [3-5]. This subunit possesses an ER retention motif in its C-terminus (RRRRR), and a di-leucine endocytic motif that may mediate its rapid, clathrin-dependent endocytosis and low steady-state plasma membrane expression. The ER retention/retrieval signal in KA2 is sterically ...
Matsushima, R., Kondo, M., Nishimura, M. and Hara-Nishimura, I. (2003), A novel ER-derived compartment, the ER body, selectively accumulates a β-glucosidase with an ER-retention signal in Arabidopsis. The Plant Journal, 33: 493-502. doi: 10.1046/j.1365-313X.2003.01636.x ...
E2F-1 is a transcription factor that is involved in cellular growth and regulates the transition between G1 and S phase during the cell cycle. However, the mechanisms by which E2F-1 regulates endoplasmic reticulum (ER) stress in ventricular myocytes remain poorly defined. ER stress was triggered by tunicamycin or thapsigargin; gene transcription was assessed by polymerase chain reaction and protein expression was detected by western blot. Cell viability and mitochondrial defects were assessed by fluorescent microscopy imaging. During ER stress, E2F-1 repressed signaling molecules of the unfolded protein response (UPR) and sensitized myocytes to cell death triggered by thapsigargin that was inhibited in Bnip3 null fibroblasts. Bnip3Δex3 rescued thapsigargin-induced cardiac apoptosis, blocked mitochondrial defects and rescued hypoxia/ER stress induced cardiac cell death. This study provides evidence that E2F-1 sensitizes ventricular myocytes to ER stress induced apoptosis 1) by repressing the ...
Unfolded proteins in the endoplasmic reticulum (ER) activate the ER transmembrane sensor Ire1 to trigger the unfolded protein response (UPR), a homeostatic signaling pathway that adjusts ER protein folding capacity according to need. Ire1 is a bifunctional enzyme, containing cytoplasmic kinase and RNase domains whose roles in signal transduction downstream of Ire1 are understood in some detail. By contrast, the question of how its ER-luminal domain (LD) senses unfolded proteins has remained an enigma. The 3.0-A crystal structure and consequent structure-guided functional analyses of the conserved core region of the LD (cLD) leads us to a proposal for the mechanism of response. cLD exhibits a unique protein fold and is sufficient to control Ire1 activation by unfolded proteins. Dimerization of cLD monomers across a large interface creates a shared central groove formed by alpha-helices that are situated on a beta-sheet floor. This groove is reminiscent of the peptide binding domains of major ...
Ca(2+) handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca(2+) homeostasis is determined by ion movements across the ER membrane, including K(+) flux through K(+) channels. We demonstrated that K(+) flux through ER-localized TALK-1 channels facilitated Ca(2+) release from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca(2+) and increased ER Ca(2+) concentrations, suggesting reduced ER Ca(2+) leak. These changes in Ca(2+) homeostasis were presumably due to TALK-1-mediated ER K(+) flux, because we recorded K(+) currents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K(+)-impermeable TALK-1 channels in HEK293 cells did not reduce ER Ca(2+) stores. Reduced ER Ca(2+) content in β cells is associated with ER stress and islet ...
A structure or part that is enclosed within its own membrane inside a cell and has a particular function. Organelles are found only in eukaryotic cells and are absent from the cells of prokaryotes such as bacteria. The nucleus, the mitochondrion, the chloroplast, the Golgi apparatus, the lysosome, and the endoplasmic reticulum are all examples of organelles. Some organelles, such as mitochondria and chloroplasts, have their own genome (genetic material) separate from that found in the nucleus of the cell. Such organelles are thought to have their evolutionary origin in symbiotic bacteria or other organisms that have become a permanent part of the cell. ...
The cortical ER network in plants is extremely dynamic with regular tubule outgrowth and transitions between tubules and cisternae being common. Based on several observations, a functional role of ER remodeling in secretion has been proposed. Actively growing and dividing cells have been shown to contain more cisternal ER than nondividing mature cells (Ridge et al., 1999), and heavily secreting root cap cells show an abundance of cisternal ER (Stephenson and Hawes, 1986). Hence, cisternalization may increase the surface area and consequently the capacity of the ER for secretion. Therefore, characterization of the key cellular players in ER remodeling, in particular those controlling tubulation versus cisternalization of the ER could have important biotechnological implications for protein production.. The relative roles of the cytoskeleton, several myosins (XIK and XIJ myosin tail domains) and Golgi bodies in these processes were recently addressed (Sparkes et al., 2009a, 2009c). To further ...
Quality control mechanisms allow only fully folded proteins to leave the ER and travel along the secretory pathway, thus ensuring the fidelity of plasma membrane and secreted proteins through which cells communicate with their environment. Misfolded proteins in the lumen or membrane of the ER are discarded by ER-associated protein degradation (ERAD), a pathway in which misfolded proteins are recognized, translocated across ER membrane (retrotranslocated), ubiquitinated and released in the cytosol for proteasomal degradation. In the recent years, we and others identified several components involved in ERAD and some aspects of the pathway have been clarified. Despite this progress, the molecular mechanisms of ERAD are still largely unknown. Key unresolved issues under investigation in our lab include the determinants for substrate selectivity and the mechanism for translocation of misfolded proteins across the ER membrane. ...
The endoplasmic reticulum (ER) is a critical organelle for protein synthesis, folding and modification, and lipid synthesis and calcium storage. Dysregulation of ER functions leads to the accumulation of misfolded- or unfolded-protein in the ER lumen, and this triggers the unfolded protein response …
The folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the ...