Faculty Opinions recommendation of The [corrected] SEC23-SEC31 [corrected] interface plays critical role for export of procollagen from the endoplasmic reticulum.

2012 ◽  
Author(s):  
David Stephens
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role

scholarly journals Craniofacial Diseases Caused by Defects in Intracellular Trafficking

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 726
Author(s):  
Chung-Ling Lu ◽  
Jinoh Kim
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Intracellular Trafficking ◽  
Critical Role ◽  
Treatment Strategies ◽  
Soluble Proteins ◽  
Genes Encoding ◽  
Membrane Bound ◽  
Signaling Receptors ◽  
Craniofacial Morphogenesis

Cells use membrane-bound carriers to transport cargo molecules like membrane proteins and soluble proteins, to their destinations. Many signaling receptors and ligands are synthesized in the endoplasmic reticulum and are transported to their destinations through intracellular trafficking pathways. Some of the signaling molecules play a critical role in craniofacial morphogenesis. Not surprisingly, variants in the genes encoding intracellular trafficking machinery can cause craniofacial diseases. Despite the fundamental importance of the trafficking pathways in craniofacial morphogenesis, relatively less emphasis is placed on this topic, thus far. Here, we describe craniofacial diseases caused by lesions in the intracellular trafficking machinery and possible treatment strategies for such diseases.

scholarly journals Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)

BMJ Open ◽  
2017 ◽  
Vol 7 (8) ◽  
pp. e015434 ◽  
Author(s):  
Eleonora Dalla Bella ◽  
Irene Tramacere ◽  
Giovanni Antonini ◽  
Giuseppe Borghero ◽  
Margherita Capasso ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyotrophic Lateral Sclerosis ◽  
Placebo Group ◽  
Phase Ii ◽  
Critical Role ◽  
Protein Translation ◽  
Phase Iii ◽  
Protein Accumulation ◽  
Neuroprotective Effects ◽  
Lateral Sclerosis

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

Localization and quantification of endoplasmic reticulum Ca(2+)-ATPase isoform transcripts

1995 ◽  
Vol 269 (3) ◽  
pp. C775-C784 ◽  
Author(s):  
K. D. Wu ◽  
W. S. Lee ◽  
J. Wey ◽  
D. Bungard ◽  
J. Lytton
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Qualitative Assessment ◽  
Cell Physiology ◽  
Striated Muscles ◽  
Physiological Processes ◽  
Alternatively Spliced ◽  
Spleen Lymphocytes ◽  
Fast Twitch ◽  
In Cells

The Ca(2+)-adenosinetriphosphatase pump of the sarcoplasmic or endoplasmic reticulum (SERCA) plays a critical role in Ca2+ signaling and homeostasis in all cells and is encoded by a family of homologous and alternatively spliced genes. To understand more clearly the role the different isoforms play in cell physiology, we have undertaken a quantitative and qualitative assessment of the tissue distribution of transcripts encoding each SERCA isoform. SERCA1 expression is restricted to fast-twitch striated muscles, SERCA2a to cardiac and slow-twitch striated muscles, whereas SERCA2b is ubiquitously expressed. SERCA3 is expressed most abundantly in large and small intestine, thymus, and cerebellum and at lower levels in spleen, lymph node, and lung. In situ hybridization analyses revealed SERCA3 transcripts in cells of the intestinal crypt, the thymic cortex, and Purkinje cells in cerebellum. In addition, SERCA3 was expressed abundantly in isolated rat spleen lymphocytes, in various murine lymphoid cell lines, and in primary cultured microvascular endothelial cells. This analysis demonstrates that SERCA3 is expressed selectively in cells in which Ca2+ signaling plays a critical and sensitive role in regulating physiological processes.

scholarly journals Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA-B27

2014 ◽  
Vol 66 (2) ◽  
pp. 284-294 ◽  
Author(s):  
Liye Chen ◽  
Roman Fischer ◽  
Yanchun Peng ◽  
Emma Reeves ◽  
Kirsty McHugh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Hla B27 ◽  
Endoplasmic Reticulum Aminopeptidase 1

scholarly journals SUN-559 Involvement of Sarco/Endoplasmic Reticulum Ca- ATPase (SERCA) in Membrane Progesterone Receptor Alpha (PAQR7)-Mediated Progesterone Induction of Vascular Smooth Muscle Relaxation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yefei Pang ◽  
Peter Thomas
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Progesterone Receptor ◽  
Protein Expression ◽  
Signaling Pathways ◽  
Muscle Relaxation ◽  
Critical Role ◽  
Akt Signaling ◽  
Membrane Progesterone Receptor ◽  
Membrane Progesterone Receptor Alpha

Abstract Progesterone (P4) exerts multiple beneficial effects on the human cardiovascular system through its actions on vascular endothelial cells and also by acting directly on vascular smooth muscle cells (VSMCs). Membrane progesterone receptor alpha (mPRα) has been shown to mediate the rapid P4-induction of human VSMC relaxation through activation of MAPK, Akt/Pi3k and RhoA/ROCK signaling pathways and the resulting reduction of calcium influx through calcium channels. In this study, we demonstrate that treatment of cultured human VSMCs with P4 for 1-2 hours increases both the mRNA and protein expression of sarco/endoplasmic reticulum Ca- ATPase (SERCA), the major transporter of calcium from the cytosol into the sarcoplasmic reticulum (SR) during muscle relaxation. Knockdown of mPRα with siRNA completely blocked this stimulatory effect of P4 as well as that of OD 02-0, a mPR selective agonist, on SERCA protein expression. In contrast, expression levels of phospholamban (PLB), a SR protein that reversibly inhibits SERCA were downregulated by this P4 treatment, and mRNA expression of a channel that releases calcium from the SR, inositol trisphosphate receptor (IP3R), was unaltered after treatment with P4. Moreover, treatments with P4 and OD 02-0, but not with R5020, a nuclear PR agonist, increased PLB phosphorylation, which would result in disinhibition of SERCA function. P4 and OD 02-0 significantly increased calcium levels in the SR detected with Fluo-5N, a specific SR calcium indicator, and caused VSMC relaxation. These effects were blocked by cyclopiazonic acid (CPA, a SERCA inhibitor), suggesting that SERCA plays a critical role in P4 induction of VSMC relaxation. Similarly, the effects of P4 and OD 02-0 on relaxation of umbilical artery rings measured with a myograph were significantly attenuated by CPA, which confirms the critical role of SERCA in the rapid action of P4 and 02-0 on vascular muscle relaxation. P4 has previously been shown to activate MAPK and Akt signaling pathways to induce VSMC relaxation. The P4- and OD 02-0-induced increases in calcium in the SR were blocked by MAPK and Akt/Pi3k signaling inhibitors, AZD6244 and wortmannin. Taken together, these results suggest that the direct, rapid effects of P4 on relaxation of VSMCs through mPRα involves regulation of the expression and function of the SR proteins SERCA and PLB through MAPK and Akt signaling pathways.

Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress

2020 ◽  
Vol 319 (6) ◽  
pp. E961-E980
Author(s):  
Ruixi Luo ◽  
Linzhao Li ◽  
Xiaohong Liu ◽  
Yujia Yuan ◽  
Wuzheng Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Mesenchymal Stem Cells ◽  
Endothelial Dysfunction ◽  
Palmitic Acid ◽  
Er Stress ◽  
Critical Role ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

High levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction (ED), which is involved in the pathogenesis of metabolic syndrome, diabetes, and atherosclerosis. Endoplasmic reticulum (ER) stress and endothelial-to-mesenchymal transition (EndMT) are demonstrated to be mechanistically related to endothelial dysfunction. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect on cellular lipotoxicity and vasculopathy. However, the underlying mechanisms have not been clearly defined. In the present study, we investigated whether MSCs could ameliorate palmitic acid (PA)-induced endothelial lipotoxicity by reducing ER stress and EndMT. We observed that MSC cocultures substantially alleviated PA-induced lipotoxicity in human umbilical vein endothelial cells (HUVECs). MSCs were able to restore the cell viability, increase tubule formation and migration ability, and decrease inflammation response and lipid deposition. Furthermore, PA caused endothelial-to-mesenchymal transition in HUVECs, which was abrogated by MSCs possibly through inhibiting ER stress. In addition, PA stimulated MSCs to secrete more stanniocalcin-1 (STC-1). Knocking down of STC-1 in MSCs attenuated their effects on PA-induced lipotoxicity in HUVECs. In vivo, MSC transplantation alleviated dyslipidemia and endothelial dysfunction in high-fat diet-fed Sprague–Dawley rats. MSC-treated rats showed reduced expressions of ER stress-related genes in aortas and suppressed expressions of EndMT-related proteins in rat aortic endothelial cells. Overall, our findings indicated that MSCs were able to attenuate endothelial lipotoxicity through inhibiting ER stress and EndMT, in which STC-1 secreted from MSCs may play a critical role.

scholarly journals The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1219 ◽  
Author(s):  
Yang Zhou ◽  
Zhizi Tong ◽  
Songhong Jiang ◽  
Wenyan Zheng ◽  
Jianjun Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Immune Defense ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Cholesterol Trafficking ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

scholarly journals Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nicholas R Guydosh ◽  
Philipp Kimmig ◽  
Peter Walter ◽  
Rachel Green
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Mrna Degradation ◽  
Ribosome Profiling ◽  
Unfolded Protein ◽  
Selective Degradation ◽  
Stressed Cells ◽  
Novel Target ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.

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