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The FEBS Journal Jan 2019Endoplasmic reticulum (ER) stress is a mechanism that allows the protection of normal cellular functions in response to both internal perturbations, such as accumulation... (Review)
Review
Endoplasmic reticulum (ER) stress is a mechanism that allows the protection of normal cellular functions in response to both internal perturbations, such as accumulation of unfolded proteins, and external perturbations, for example redox stress, UVB irradiation, and infection. A hallmark of ER stress is the accumulation of misfolded and unfolded proteins. Physiological levels of ER stress trigger the unfolded protein response (UPR) that is required to restore normal ER functions. However, the UPR can also initiate a cell death program/apoptosis pathway in response to excessive or persistent ER stress. Recently, it has become evident that chronic ER stress occurs in several diseases, including skin diseases such as Darier's disease, rosacea, vitiligo and melanoma; furthermore, it is suggested that ER stress is directly involved in the pathogenesis of these disorders. Here, we review the role of ER stress in skin function, and discuss its significance in skin diseases.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Protein Folding; Signal Transduction; Skin; Skin Diseases; Unfolded Protein Response
PubMed: 30586218
DOI: 10.1111/febs.14739 -
Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview.American Journal of Physiology. Cell... Oct 2014Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR... (Review)
Review
Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases.
Topics: Animals; Apoptosis; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Gene Expression Regulation; Humans; Proteins; Signal Transduction; Unfolded Protein Response
PubMed: 25143348
DOI: 10.1152/ajpcell.00258.2014 -
Progress in Molecular and Subcellular... 2021Molecular chaperones assist the folding of nascent chains in the cell. Chaperones also aid in quality control decisions as persistent chaperone binding can help to sort...
Molecular chaperones assist the folding of nascent chains in the cell. Chaperones also aid in quality control decisions as persistent chaperone binding can help to sort terminal misfolded proteins for degradation. There are two major molecular chaperone families in the endoplasmic reticulum (ER) that assist proteins in reaching their native structure and evaluating the fidelity of the maturation process. The ER Hsp70 chaperone, BiP, supports adenine nucleotide-regulated binding to non-native proteins that possess exposed hydrophobic regions. In contrast, the carbohydrate-dependent chaperone system involving the membrane protein calnexin and its soluble paralogue calreticulin recognize a specific glycoform of an exposed hydrophilic protein modification for which the composition is controlled by a series of glycosidases and transferases. Here, we compare and contrast the properties, mechanisms of action and functions of these different chaperones systems that work in parallel, as well as together, to assist a large variety of substrates that traverse the eukaryotic secretory pathway.
Topics: Calnexin; Endoplasmic Reticulum; Molecular Chaperones; Protein Folding; Quality Control
PubMed: 34050861
DOI: 10.1007/978-3-030-67696-4_3 -
IUBMB Life Jun 2015The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such... (Review)
Review
The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking, and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them toward ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion, and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the unfolded protein response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease.
Topics: Amyloidogenic Proteins; Amyloidosis; Endoplasmic Reticulum; Humans; Protein Folding; Protein Stability; Protein Transport; Signal Transduction; Unfolded Protein Response
PubMed: 26018985
DOI: 10.1002/iub.1386 -
Journal of Lipid Research Apr 2009This review presents an overview of mammalian phospholipid synthesis and the cellular locations of the biochemical activities that produce membrane lipid molecular... (Review)
Review
This review presents an overview of mammalian phospholipid synthesis and the cellular locations of the biochemical activities that produce membrane lipid molecular species. The generalized endoplasmic reticulum compartment is a central site for membrane lipid biogenesis, and examples of the emerging relationships between alterations in lipid composition, regulation of membrane lipid biogenesis, and cellular secretory function are discussed.
Topics: Animals; Endoplasmic Reticulum; Golgi Apparatus; Membrane Lipids; Phospholipids
PubMed: 18952570
DOI: 10.1194/jlr.R800049-JLR200 -
Cold Spring Harbor Perspectives in... Jan 2013To cause infection, a virus enters a host cell, replicates, and assembles, with the resulting new viral progeny typically released into the extracellular environment to... (Review)
Review
To cause infection, a virus enters a host cell, replicates, and assembles, with the resulting new viral progeny typically released into the extracellular environment to initiate a new infection round. Virus entry, replication, and assembly are dynamic and coordinated processes that require precise interactions with host components, often within and surrounding a defined subcellular compartment. Accumulating evidence pinpoints the endoplasmic reticulum (ER) as a crucial organelle supporting viral entry, replication, and assembly. This review focuses on the molecular mechanism by which different viruses co-opt the ER to accomplish these crucial infection steps. Certain bacterial toxins also hijack the ER for entry. An interdisciplinary approach, using rigorous biochemical and cell biological assays coupled with advanced microscopy strategies, will push to the next level our understanding of the virus-ER interaction during infection.
Topics: Cholera Toxin; Endoplasmic Reticulum; Host-Pathogen Interactions; Immune Evasion; Models, Biological; Polyomavirus; Virus Assembly; Virus Internalization; Virus Replication
PubMed: 23284050
DOI: 10.1101/cshperspect.a013250 -
Biological & Pharmaceutical Bulletin 2020Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC)... (Review)
Review
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptide-processing enzyme, specifically emphasizing on its secretory form.
Topics: Aminopeptidases; Animals; Endoplasmic Reticulum; Humans
PubMed: 32009107
DOI: 10.1248/bpb.b19-00857 -
Nature Reviews. Microbiology Feb 2015The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the... (Review)
Review
The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria.
Topics: Animals; Bacteria; Bacterial Infections; Cell Proliferation; Endoplasmic Reticulum; Immunity, Innate; Unfolded Protein Response
PubMed: 25534809
DOI: 10.1038/nrmicro3393 -
Experimental Cell Research Jul 2012The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of... (Review)
Review
The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of curvature stabilizing proteins, the reticulons and DP1; however it is still unclear how the sheets are assembled. The ER is the cellular compartment responsible for secretory and membrane protein synthesis. The reducing conditions of ER lead to the intra/inter-chain formation of new disulphide bonds into polypeptides during protein folding assessed by enzymatic or spontaneous reactions. Moreover, ER represents the main intracellular calcium storage site and it plays an important role in calcium signaling that impacts many cellular processes. Accordingly, the maintenance of ER function represents an essential condition for the cell, and ER morphology constitutes an important prerogative of it. Furthermore, it is well known that ER undergoes prominent shape transitions during events such as cell division and differentiation. Thus, maintaining the correct ER structure is an essential feature for cellular physiology. Now, it is known that proper ER-associated proteins play a fundamental role in ER tubules formation. Among these ER-shaping proteins are the reticulons (RTN), which are acquiring a relevant position. In fact, beyond the structural role of reticulons, in very recent years new and deeper functional implications of these proteins are emerging in relation to their involvement in several cellular processes.
Topics: Animals; Calcium; Endoplasmic Reticulum; Humans; Membrane Proteins; Protein Folding
PubMed: 22425683
DOI: 10.1016/j.yexcr.2012.03.002 -
Cold Spring Harbor Perspectives in... May 2019The endoplasmic reticulum (ER) is a dynamic organelle responsible for many cellular functions in eukaryotic cells. Proper redox conditions in the ER are necessary for... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic organelle responsible for many cellular functions in eukaryotic cells. Proper redox conditions in the ER are necessary for the functions of many luminal pathways and the maintenance of homeostasis. The redox environment in the ER is oxidative compared with that of the cytosol, and a network of oxidoreductases centering on the protein disulfide isomerase (PDI)-Ero1α hub complex is constructed for efficient electron transfer. Although these oxidizing environments are advantageous for oxidative folding for protein maturation, electron transfer is strictly controlled by Ero1α structurally and spatially. The ER redox environment shifts to a reductive environment under certain stress conditions. In this review, we focus on the reducing reactions that maintain ER homeostasis and introduce their significance in an oxidative ER environment.
Topics: Animals; Endoplasmic Reticulum; Gene Expression Regulation; Homeostasis; Oxidation-Reduction; Protein Folding
PubMed: 30396882
DOI: 10.1101/cshperspect.a033910