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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?
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Endoplasmic reticulum quality control in lipoprotein metabolism.
Koerner, CM, Roberts, BS, Neher, SB
Molecular and cellular endocrinology. 2019;:110547
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Abstract
Lipids play a critical role in energy metabolism, and a suite of proteins is required to deliver lipids to tissues. Several of these proteins require an intricate endoplasmic reticulum (ER) quality control (QC) system and unique secondary chaperones for folding. Key examples include apolipoprotein B (apoB), which is the primary scaffold for many lipoproteins, dimeric lipases, which hydrolyze triglycerides from circulating lipoproteins, and the low-density lipoprotein receptor (LDLR), which clears cholesterol-rich lipoproteins from the circulation. ApoB requires specialized proteins for lipidation, dimeric lipases lipoprotein lipase (LPL) and hepatic lipase (HL) require a transmembrane maturation factor for secretion, and the LDLR requires several specialized, domain-specific chaperones. Deleterious mutations in these proteins or their chaperones may result in dyslipidemias, which are detrimental to human health. Here, we review the ER quality control systems that ensure secretion of apoB, LPL, HL, and LDLR with a focus on the specialized chaperones required by each protein.
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STIM1 activation of Orai1.
Lunz, V, Romanin, C, Frischauf, I
Cell calcium. 2019;:29-38
Abstract
A primary calcium (Ca2+) entry pathway into non-excitable cells is through the store-operated Ca2+ release activated Ca2+ (CRAC) channel. Ca2+ entry into cells is responsible for the initiation of diverse signalling cascades that affect essential cellular processes like gene regulation, cell growth and death, secretion and gene transcription. Upon depletion of intracellular Ca2+ stores within the endoplasmic reticulum (ER), the CRAC channel opens to refill depleted stores. The two key limiting molecular players of the CRAC channel are the stromal interaction molecule (STIM1) embedded in the ER-membrane and Orai1, residing in the plasma membrane (PM), respectively. Together, they form a highly Ca2+ selective ion channel complex. STIM1 senses the Ca2+ content of the ER and confers Ca2+ store-depletion into the opening of Orai1 channels in the PM for triggering Ca2+-dependent gene transcription, T-cell activation or mast cell degranulation. The interplay of Orai and STIM proteins in the CRAC channel signalling cascade has been the main focus of research for more than twelve years. This chapter focuses on current knowledge and main experimental advances in the understanding of Orai1 activation by STIM1, thereby portraying key mechanistic steps in the CRAC channel signalling cascade.
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Extended synaptotagmins, peroxisome-endoplasmic reticulum contact and cholesterol transport.
Yang, H
Science China. Life sciences. 2019;(9):1266-1269
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ER-mitochondria interactions: Both strength and weakness within cancer cells.
Doghman-Bouguerra, M, Lalli, E
Biochimica et biophysica acta. Molecular cell research. 2019;(4):650-662
Abstract
ER-mitochondria contact sites represent hubs for signaling that control mitochondrial biology related to several aspects of cellular survival, metabolism, cell death sensitivity and metastasis, which all contribute to tumorigenesis. Altered ER-mitochondria contacts can deregulate Ca2+ homeostasis, phospholipid metabolism, mitochondrial morphology and dynamics. MAM represent both a hot spot in cancer onset and progression and an Achilles' heel of cancer cells that can be exploited for therapeutic perspectives. Over the past years, an increasing number of cancer-related proteins, including oncogenes and tumor suppressors, have been localized in MAM and exert their pro- or antiapoptotic functions through the regulation of Ca2+ transfer and signaling between the two organelles. In this review, we highlight the central role of ER-mitochondria contact sites in tumorigenesis and focus on chemotherapeutic drugs or potential targets that act on MAM properties for new therapeutic approaches in cancer.
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Mechanistic Connections between Endoplasmic Reticulum (ER) Redox Control and Mitochondrial Metabolism.
Fan, Y, Simmen, T
Cells. 2019;(9)
Abstract
The past decade has seen the emergence of endoplasmic reticulum (ER) chaperones as key determinants of contact formation between mitochondria and the ER on the mitochondria-associated membrane (MAM). Despite the known roles of ER-mitochondria tethering factors like PACS-2 and mitofusin-2, it is not yet entirely clear how they mechanistically interact with the ER environment to determine mitochondrial metabolism. In this article, we review the mechanisms used to communicate ER redox and folding conditions to the mitochondria, presumably with the goal of controlling mitochondrial metabolism at the Krebs cycle and at the electron transport chain, leading to oxidative phosphorylation (OXPHOS). To achieve this goal, redox nanodomains in the ER and the interorganellar cleft influence the activities of ER chaperones and Ca2+-handling proteins to signal to mitochondria. This mechanism, based on ER chaperones like calnexin and ER oxidoreductases like Ero1α, controls reactive oxygen production within the ER, which can chemically modify the proteins controlling ER-mitochondria tethering, or mitochondrial membrane dynamics. It can also lead to the expression of apoptotic or metabolic transcription factors. The link between mitochondrial metabolism and ER homeostasis is evident from the specific functions of mitochondria-ER contact site (MERC)-localized Ire1 and PERK. These functions allow these two transmembrane proteins to act as mitochondria-preserving guardians, a function that is apparently unrelated to their functions in the unfolded protein response (UPR). In scenarios where ER stress cannot be resolved via the activation of mitochondrial OXPHOS, MAM-localized autophagosome formation acts to remove defective portions of the ER. ER chaperones such as calnexin are again critical regulators of this MERC readout.
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Fine-tuning of store-operated calcium entry by fast and slow Ca2+-dependent inactivation: Involvement of SARAF.
Jardín, I, Albarran, L, Salido, GM, López, JJ, Sage, SO, Rosado, JA
Biochimica et biophysica acta. Molecular cell research. 2018;(3):463-469
Abstract
Store-operated Ca2+ entry (SOCE) is a functionally relevant mechanism for Ca2+ influx present in electrically excitable and non-excitable cells. Regulation of Ca2+ entry through store-operated channels is essential to maintain an appropriate intracellular Ca2+ homeostasis and prevent cell damage. Calcium-release activated channels exhibit Ca2+-dependent inactivation mediated by two temporally separated mechanisms: fast Ca2+-dependent inactivation takes effect in the order of milliseconds and involves the interaction of Ca2+ with residues in the channel pore while slow Ca2+-dependent inactivation (SCDI) develops over tens of seconds, requires a global rise in [Ca2+]cyt and is a mechanism regulated by mitochondria. Recent studies have provided evidence that the protein SARAF (SOCE-associated regulatory factor) is involved in the mechanism underlying SCDI of Orai1. SARAF is an endoplasmic reticulum (ER) membrane protein that associates with STIM1 and translocate to plasma membrane-ER junctions in a STIM1-dependent manner upon store depletion to modulate SOCE. SCDI mediated by SARAF depends on the location of the STIM1-Orai1 complex within a PI(4,5)P2-rich microdomain. SARAF also interacts with Orai1 and TRPC1 in cells endogenously expressing STIM1 and cells with a low STIM1 expression and modulates channel function. This review focuses on the modulation by SARAF of SOCE and other forms of Ca2+ influx mediated by Orai1 and TRPC1 in order to provide spatio-temporally regulated Ca2+ signals.
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Roles for ER:endosome membrane contact sites in ligand-stimulated intraluminal vesicle formation.
Wong, LH, Eden, ER, Futter, CE
Biochemical Society transactions. 2018;(5):1055-1062
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Abstract
Multivesicular endosomes/bodies (MVBs) sort membrane proteins between recycling and degradative pathways. Segregation of membrane proteins onto intraluminal vesicles (ILVs) of MVBs removes them from the recycling pathway and facilitates their degradation following fusion of MVBs with lysosomes. Sorting of many cargos onto ILVs depends on the ESCRT (Endosomal Sorting Complex Required for Transport) machinery, although ESCRT-independent mechanisms also exist. In mammalian cells, efficient sorting of ligand-stimulated epidermal growth factor receptors onto ILVs also depends on the tyrosine phosphatase, PTP1B, an ER-localised enzyme that interacts with endosomal targets at membrane contacts between MVBs and the ER. This review focuses on the potential roles played by ER:MVB membrane contact sites in regulating ESCRT-dependent ILV formation.
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Ca2+ and lipid signals hold hands at endoplasmic reticulum-plasma membrane contact sites.
Balla, T
The Journal of physiology. 2018;(14):2709-2716
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Discovery of the STIM1 and Orai proteins as the principal components of store-operated Ca2+ entry has drawn attention to contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM). Such contacts between adjacent membranes of different cellular organelles, primarily between the mitochondria and the ER, had already been known as the sites where Ca2+ released from the ER can be efficiently channelled to the mitochondria and also where phosphatidylserine synthesis and transfer takes place. Recent studies have identified contact sites between virtually every organelle and the ER and the functional importance of these small specialized membrane domains is increasingly recognized. Most recent developments have highlighted the role of phosphatidylinositol 4-phosphate gradients as critical determinants of the non-vesicular transport of various lipids from the ER to other organelles such as the Golgi or PM. As we learn more about membrane contact sites it becomes apparent that Ca2+ is not only transported at these sites but also controls both the dynamics and the lipid transfer efficiency of these processes. Conversely, lipids are critical for regulating the Ca2+ entry process. This review will summarize some of the most exciting recent developments in this rapidly expanding research field.
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Cytokinin signaling: from the ER or from the PM? That is the question!
Romanov, GA, Lomin, SN, Schmülling, T
The New phytologist. 2018;(1):41-53
Abstract
Content Summary 47 I. Introduction 47 II. Historical outline 48 III. Recent developments 49 IV. Towards an integrative concept for cytokinin receptor signaling 54 Acknowledgements 57 References 57 SUMMARY Cytokinin signaling plays an important role in plant growth and development, and therefore its molecular characteristics are under extensive study. One characteristic is the subcellular localization of cytokinin signal initiation. This localization determines both the pathway for hormone delivery to the receptor, as well as molecular aspects of signal transfer to the primary cellular targets. Subcellular sites for the onset of cytokinin signaling are still uncertain and experimental data are in part controversial. A few years ago, cytokinin receptors were shown to be localized predominantly in the membrane of the endoplasmic reticulum (ER) and to possess some features, such as their pH activity profile, typical for intracellular proteins. Very recently, new data corroborating the functionality of ER-located cytokinin receptors were reported. However, other work argued for cytokinin perception to occur at the plasma membrane (PM). Here, we discuss in detail these partially conflicting data and present an integrative model for cytokinin perception and signaling. In our opinion, the prevailing evidence argues for the ER being the predominant site of cytokinin signal perception but also that signal initiation at the PM might be relevant in some circumstances as well. The roles of these pathways in long-distance, paracrine and autocrine cytokinin signaling are discussed.