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The Endoplasmic Reticulum-Plasma Membrane Junction: A Hub for Agonist Regulation of Ca2+ Entry.
Ong, HL, Ambudkar, IS
Cold Spring Harbor perspectives in biology. 2020;(2)
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Abstract
Stimulation of cell-surface receptors induces cytosolic Ca2+ ([Ca2+]i) increases that are detected and transduced by effector proteins for regulation of cell function. Intracellular Ca2+ release, via endoplasmic reticulum (ER) proteins inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), and Ca2+ influx, via store-operated Ca2+ entry (SOCE), contribute to the increase in [Ca2+]i The amplitude, frequency, and spatial characteristics of the [Ca2+]i increases are controlled by the compartmentalization of proteins into signaling complexes such as receptor-signaling complexes and SOCE complexes. Both complexes include protein and lipid components, located in the plasma membrane (PM) and ER. Receptor signaling initiates in the PM via phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), and culminates with the activation of IP3R in the ER. Conversely, SOCE is initiated in the ER by Ca2+-sensing stromal interaction molecule (STIM) proteins, which then interact with PM channels Orai1 and TRPC1 to activate Ca2+ entry. This review will address how ER-PM junctions serve a central role in agonist regulation of SOCE.
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The mystery of mitochondria-ER contact sites in physiology and pathology: A cancer perspective.
Simoes, ICM, Morciano, G, Lebiedzinska-Arciszewska, M, Aguiari, G, Pinton, P, Potes, Y, Wieckowski, MR
Biochimica et biophysica acta. Molecular basis of disease. 2020;(10):165834
Abstract
Mitochondria-associated membranes (MAM), physical platforms that enable communication between mitochondria and the endoplasmic reticulum (ER), are enriched with many proteins and enzymes involved in several crucial cellular processes, such as calcium (Ca2+) homeostasis, lipid synthesis and trafficking, autophagy and reactive oxygen species (ROS) production. Accumulating studies indicate that tumor suppressors and oncogenes are present at these intimate contacts between mitochondria and the ER, where they influence Ca2+ flux between mitochondria and the ER or affect lipid homeostasis at MAM, consequently impacting cell metabolism and cell fate. Understanding these fundamental roles of mitochondria-ER contact sites as important domains for tumor suppressors and oncogenes can support the search for new and more precise anticancer therapies. In the present review, we summarize the current understanding of basic MAM biology, composition and function and discuss the possible role of MAM-resident oncogenes and tumor suppressors.
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Endoplasmic Reticulum Calcium Pumps and Tumor Cell Differentiation.
Papp, B, Launay, S, Gélébart, P, Arbabian, A, Enyedi, A, Brouland, JP, Carosella, ED, Adle-Biassette, H
International journal of molecular sciences. 2020;(9)
Abstract
Endoplasmic reticulum (ER) calcium homeostasis plays an essential role in cellular calcium signaling, intra-ER protein chaperoning and maturation, as well as in the interaction of the ER with other organelles. Calcium is accumulated in the ER by sarco/endoplasmic reticulum calcium ATPases (SERCA enzymes) that generate by active, ATP-dependent transport, a several thousand-fold calcium ion concentration gradient between the cytosol (low nanomolar) and the ER lumen (high micromolar). SERCA enzymes are coded by three genes that by alternative splicing give rise to several isoforms, which can display isoform-specific calcium transport characteristics. SERCA expression levels and isoenzyme composition vary according to cell type, and this constitutes a mechanism whereby ER calcium homeostasis is adapted to the signaling and metabolic needs of the cell, depending on its phenotype, its state of activation and differentiation. As reviewed here, in several normal epithelial cell types including bronchial, mammary, gastric, colonic and choroid plexus epithelium, as well as in mature cells of hematopoietic origin such as pumps are simultaneously expressed, whereas in corresponding tumors and leukemias SERCA3 expression is selectively down-regulated. SERCA3 expression is restored during the pharmacologically induced differentiation of various cancer and leukemia cell types. SERCA3 is a useful marker for the study of cell differentiation, and the loss of SERCA3 expression constitutes a previously unrecognized example of the remodeling of calcium homeostasis in tumors.
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Lessons from the Endoplasmic Reticulum Ca2+ Transporters-A Cancer Connection.
Zhai, X, Sterea, AM, Hiani, YE
Cells. 2020;(6)
Abstract
Ca2+ is an integral mediator of intracellular signaling, impacting almost every aspect of cellular life. The Ca2+-conducting transporters located on the endoplasmic reticulum (ER) membrane shoulder the responsibility of constructing the global Ca2+ signaling landscape. These transporters gate the ER Ca2+ release and uptake, sculpt signaling duration and intensity, and compose the Ca2+ signaling rhythm to accommodate a plethora of biological activities. In this review, we explore the mechanisms of activation and functional regulation of ER Ca2+ transporters in the establishment of Ca2+ homeostasis. We also contextualize the aberrant alterations of these transporters in carcinogenesis, presenting Ca2+-based therapeutic interventions as a means to tackle malignancies.
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ER-Golgi membrane contact sites.
Venditti, R, Masone, MC, De Matteis, MA
Biochemical Society transactions. 2020;(1):187-197
Abstract
Membrane contact sites (MCSs) are sites where the membranes of two different organelles come into close apposition (10-30 nm). Different classes of proteins populate MCSs including factors that act as tethers between the two membranes, proteins that use the MCSs for their function (mainly lipid or ion exchange), and regulatory proteins and enzymes that can act in trans across the MCSs. The ER-Golgi MCSs were visualized by electron microscopists early in the sixties but have remained elusive for decades due to a lack of suitable methodological approaches. Here we report recent progress in the study of this class of MCSs that has led to the identification of their main morphological features and of some of their components and roles. Among these, lipid transfer proteins and lipid exchange have been the most studied and understood so far. However, many unknowns remain regarding their regulation and their role in controlling key TGN functions such as sorting and trafficking as well as their relevance in physiological and pathological conditions.
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Interplay between endoplasmic reticulum membrane contacts and actomyosin cytoskeleton.
Zhang, D
Cytoskeleton (Hoboken, N.J.). 2020;(7):241-248
Abstract
Eukaryotic membrane-bound organelles, exhibiting distinctive morphologies, dynamics and functions, are interconnected at membrane contact sites (MCSs) through numerous tethering machineries. MCSs are required for many fundamental cellular processes, such as non-vesicular lipid transfer, calcium transport and organelle homeostasis. Actin cytoskeleton and myosin motors are known to dynamically interact with different membrane boundaries, facilitating organelle movements and partitioning. Intriguingly, recent studies have pinpointed a special participation of actomyosin at various MCSs involving the endoplasmic reticulum (ER), the most extensive membranous organelle in the cell. Here, I summarize emerging roles of ER MCSs in modulating actomyosin structures and discuss feedback functions of such actomyosin regulation at these MCSs.
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Isolation, Purity Assessment, and Proteomic Analysis of Endoplasmic Reticulum.
Wang, X, Komatsu, S
Methods in molecular biology (Clifton, N.J.). 2020;:117-131
Abstract
Subcellular proteomics include, in its experimental workflow, steps aimed at purifying organelles. The purity of the subcellular fraction should be assessed before mass spectrometry analysis, in order to confidently conclude the presence of associated specific proteoforms, deepening the knowledge of its biological function. In this chapter, a protocol for isolating endoplasmic reticulum (ER) and purity assessment is reported, and it precedes the proteomic analysis through a gel-free/label-free proteomic approach. Dysfunction of quality-control mechanisms of protein metabolism in ER leads to ER stress. Additionally, ER, which is a calcium-storage organelle, is responsible for signaling and homeostatic function, and calcium homeostasis is required for plant tolerance. With such predominant cell functions, effective protocols to fractionate highly purified ER are needed. Here, isolation methods and purity assessments of ER are described. In addition, a gel-free/label-free proteomic approach of ER is presented.
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The role of sphingolipids in endoplasmic reticulum stress.
Park, WJ, Park, JW
FEBS letters. 2020;(22):3632-3651
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Abstract
The endoplasmic reticulum (ER) is an important intracellular compartment in eukaryotic cells and has diverse functions, including protein synthesis, protein folding, lipid metabolism and calcium homeostasis. ER functions are disrupted by various intracellular and extracellular stimuli that cause ER stress, including the inhibition of glycosylation, disulphide bond reduction, ER calcium store depletion, impaired protein transport to the Golgi, excessive ER protein synthesis, impairment of ER-associated protein degradation and mutated ER protein expression. Distinct ER stress signalling pathways, which are known as the unfolded protein response, are deployed to maintain ER homeostasis, and a failure to reverse ER stress triggers cell death. Sphingolipids are lipids that are structurally characterized by long-chain bases, including sphingosine or dihydrosphingosine (also known as sphinganine). Sphingolipids are bioactive molecules long known to regulate various cellular processes, including cell proliferation, migration, apoptosis and cell-cell interaction. Recent studies have uncovered that specific sphingolipids are involved in ER stress. This review summarizes the roles of sphingolipids in ER stress and human diseases in the context of pathogenic events.
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ER functions are exploited by viruses to support distinct stages of their life cycle.
Chen, YJ, Bagchi, P, Tsai, B
Biochemical Society transactions. 2020;(5):2173-2184
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Abstract
The endoplasmic reticulum (ER), with its expansive membranous system and a vast network of chaperones, enzymes, sensors, and ion channels, orchestrates diverse cellular functions, ranging from protein synthesis, folding, secretion, and degradation to lipid biogenesis and calcium homeostasis. Strikingly, some of the functions of the ER are exploited by viruses to promote their life cycles. During entry, viruses must penetrate a host membrane and reach an intracellular destination to express and replicate their genomes. These events lead to the assembly of new viral progenies that exit the host cell, thereby initiating further rounds of infection. In this review, we highlight how three distinct viruses - polyomavirus, flavivirus, and coronavirus - co-opt key functions of the ER to cause infection. We anticipate that illuminating this virus-ER interplay will provide rational therapeutic approaches to combat the virus-induced diseases.
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Unfolded Protein Response: Cause or Consequence of Lipid and Lipoprotein Metabolism Disturbances?
Pinto, BAS, França, LM, Laurindo, FRM, Paes, AMA
Advances in experimental medicine and biology. 2019;:67-82
Abstract
The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?