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Current Biology : CB Feb 2014Endoplasmic reticulum (ER) to Golgi trafficking is an essential step in sorting mature, correctly folded, processed and assembled proteins (cargo) from immature proteins... (Review)
Review
Endoplasmic reticulum (ER) to Golgi trafficking is an essential step in sorting mature, correctly folded, processed and assembled proteins (cargo) from immature proteins and ER-resident proteins. However, the mechanisms governing trafficking selectivity, specificity and regulation are not yet fully understood. To date, three complementary mechanisms have been described that enable regulation of this trafficking step: ER retention of immature proteins in the ER; selective uptake of fully mature proteins into Golgi-bound vesicles; and retrieval from the Golgi of immature cargo that has erroneously exited the ER. Together, these three mechanisms allow incredible specificity and enable the cell to carry out protein quality control and regulate protein processing, oligomerization and expression. This review will focus on the current knowledge of selectivity mechanisms acting during the ER-to-Golgi sorting step and their significance in health and disease. The review will also highlight several key questions that have remained unanswered and discuss the future frontiers.
Topics: Animals; Endoplasmic Reticulum; Golgi Apparatus; Humans; Protein Transport
PubMed: 24502791
DOI: 10.1016/j.cub.2013.12.008 -
International Review of Cell and... 2013The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness.... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Proteolysis; Unfolded Protein Response
PubMed: 23317820
DOI: 10.1016/B978-0-12-407704-1.00005-1 -
European Respiratory Review : An... Jun 2017Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled... (Review)
Review
Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Environmental Pollutants; Humans; Inhalation Exposure; Lung; Lung Neoplasms; Pulmonary Fibrosis; Signal Transduction; Smoking; Unfolded Protein Response
PubMed: 28659504
DOI: 10.1183/16000617.0018-2017 -
Biochimica Et Biophysica Acta Nov 2013The endoplasmic reticulum (ER) is an interconnected network of tubular and planar membranes that supports the synthesis and export of proteins, carbohydrates and lipids.... (Review)
Review
The endoplasmic reticulum (ER) is an interconnected network of tubular and planar membranes that supports the synthesis and export of proteins, carbohydrates and lipids. Phospholipids, in particular phosphatidylcholine (PC), are synthesized in the ER where they have essential functions including provision of membranes required for protein synthesis and export, cholesterol homeostasis, and triacylglycerol storage and secretion. Coordination of these biological processes is essential, as highlighted by findings that link phospholipid metabolism in the ER with perturbations in lipid storage/secretion and stress responses, ultimately contributing to obesity/diabetes, atherosclerosis and neurological disorders. Phospholipid synthesis is not uniformly distributed in the ER but is localized at membrane interfaces or contact zones with other organelles, and in dynamic, proliferating ER membranes. The topology of phospholipid synthesis is an important consideration when establishing the etiology of diseases that arise from ER dysfunction. This review will highlight our current understanding of the contribution of phospholipid synthesis to proper ER function, and how alterations contribute to aberrant stress responses and disease. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Topics: Animals; Biological Transport; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Lipid Metabolism; Phospholipids
PubMed: 23711956
DOI: 10.1016/j.bbamcr.2013.05.018 -
The Journal of Investigative Dermatology Sep 2016Ca(2+) fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca(2+)... (Review)
Review
Ca(2+) fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca(2+) stores constitute a major portion of the calcium gradient especially in the stratum granulosum. Loss of the calcium gradient triggers epidermal barrier homeostatic responses. In this report, using unfixed ex vivo epidermis and human epidermal equivalents we show that endoplasmic reticulum (ER) Ca(2+) is released in response to barrier perturbation, and that this release constitutes the major shift in epidermal Ca(2+) seen after barrier perturbation. We find that ER Ca(2+) release correlates with a transient increase in extracellular Ca(2+). Lastly, we show that ER calcium release resulting from barrier perturbation triggers transient desmosomal remodeling, seen as an increase in extracellular space and a loss of the desmosomal intercellular midline. Topical application of thapsigargin, which inhibits the ER Ca(2+) ATPase activity without compromising barrier integrity, also leads to desmosomal remodeling and loss of the midline structure. These experiments establish the ER Ca(2+) store as a master regulator of the Ca(2+) gradient response to epidermal barrier perturbation, and suggest that ER Ca(2+) homeostasis also modulates normal desmosomal reorganization, both at rest and after acute barrier perturbation.
Topics: Animals; Biopsy, Needle; Calcium; Cell Membrane Permeability; Desmosomes; Endoplasmic Reticulum; Epidermis; Homeostasis; Humans; Immunohistochemistry; Skin Absorption; Thapsigargin
PubMed: 27255610
DOI: 10.1016/j.jid.2016.05.100 -
Cells Sep 2019Efficiency and fidelity of protein secretion are achieved thanks to the presence of different steps, located sequentially in time and space along the secretory... (Review)
Review
Efficiency and fidelity of protein secretion are achieved thanks to the presence of different steps, located sequentially in time and space along the secretory compartment, controlling protein folding and maturation. After entering into the endoplasmic reticulum (ER), secretory proteins attain their native structure thanks to specific chaperones and enzymes. Only correctly folded molecules are allowed by quality control (QC) mechanisms to leave the ER and proceed to downstream compartments. Proteins that cannot fold properly are instead retained in the ER to be finally destined to proteasomal degradation. Exiting from the ER requires, in most cases, the use of coated vesicles, departing at the ER exit sites, which will fuse with the Golgi compartment, thus releasing their cargoes. Protein accumulation in the ER can be caused by a too stringent QC or by ineffective transport: these situations could be deleterious for the organism, due to the loss of the secreted protein, and to the cell itself, because of abnormal increase of protein concentration in the ER. In both cases, diseases can arise. In this review, we will describe the pathophysiology of protein folding and transport between the ER and the Golgi compartment.
Topics: Biological Transport; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Protein Folding; Protein Transport; Proteins
PubMed: 31500301
DOI: 10.3390/cells8091051 -
International Journal of Molecular... Nov 2019Cellular activities, such as growth and secretion, are dependent on correct protein folding and intracellular protein transport. Injury, like ischemia, malnutrition, and... (Review)
Review
Cellular activities, such as growth and secretion, are dependent on correct protein folding and intracellular protein transport. Injury, like ischemia, malnutrition, and invasion of toxic substances, affect the folding environment in the endoplasmic reticulum (ER). The ER senses this information, following which cells adapt their response to varied situations through the unfolded protein response. Activation of the KDEL receptor, resulting from the secretion from the ER of chaperones containing the KDEL sequence, plays an important role in this adaptation. The KDEL receptor was initially shown to be necessary for the retention of KDEL sequence-containing proteins in the ER. However, it has become clear that the activated KDEL receptor also regulates bidirectional transport between the ER and the Golgi complex, as well as from the Golgi to the secretory pathway. In addition, it has been suggested that the signal for KDEL receptor activation may also affect several other cellular activities. In this review, we discuss KDEL receptor-mediated bidirectional transport and signaling and describe disease models and human diseases related to KDEL receptor dysfunction.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Golgi Apparatus; Humans; Protein Transport; Proteostasis; Receptors, Peptide; Signal Transduction; Unfolded Protein Response
PubMed: 31717602
DOI: 10.3390/ijms20225614 -
Current Opinion in Cell Biology Aug 2020Misfolded and mistargeted proteins in the early secretory pathway present significant risks to the cell. A diverse and integrated network of quality control pathways... (Review)
Review
Misfolded and mistargeted proteins in the early secretory pathway present significant risks to the cell. A diverse and integrated network of quality control pathways protects the cell from these threats. We focus on the discovery of new mechanisms that contribute to this protective network. Biochemical and structural advances in endoplasmic reticulum targeting fidelity, and in the redistribution of mistargeted substrates are discussed. We further review new discoveries in quality control at the inner nuclear membrane in the context of orphaned subunits. We consider developments in our understanding of cargo selection for endoplasmic reticulum export. Conflicting data on quality control by cargo receptor proteins are discussed and we look to important future questions for the field.
Topics: Endoplasmic Reticulum; Humans; Membrane Proteins; Models, Biological; Protein Folding; Secretory Pathway
PubMed: 32408120
DOI: 10.1016/j.ceb.2020.04.002 -
The FEBS Journal Jan 2019Various types of intracellular and extracellular stresses disturb homeostasis in the endoplasmic reticulum (ER) and, thus, trigger the ER stress response. Unavoidable... (Review)
Review
Various types of intracellular and extracellular stresses disturb homeostasis in the endoplasmic reticulum (ER) and, thus, trigger the ER stress response. Unavoidable and/or prolonged ER stress causes cell toxicity and occasionally cell death. The malfunction or death of irreplaceable cells leads to conformational diseases, including diabetes mellitus, ischemic diseases, metabolic diseases, and neurodegenerative diseases. In the past several decades, many studies have revealed the molecular mechanisms of the ER quality control system. Cells resolve ER stress by promptly and accurately reducing the amount of malfolded proteins. Recent reports have revealed that cells possess several types of ER-related disposal systems, including mRNA decay, proteasomal degradation, and autophagy. The removal of dispensable RNAs, proteins, and organelle parts may enable the effective maintenance of a functional ER. Here, we provide a comprehensive understanding of the ER quality control system by focusing on ER-related garbage disposal systems.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Humans; Proteasome Endopeptidase Complex; Protein Folding; Quality Control
PubMed: 29923316
DOI: 10.1111/febs.14589 -
The New Phytologist Apr 2020Secretory and transmembrane protein synthesis and initial modification are essential processes in protein maturation, and these processes are important for maintaining... (Review)
Review
Secretory and transmembrane protein synthesis and initial modification are essential processes in protein maturation, and these processes are important for maintaining protein homeostasis in the endoplasmic reticulum (ER). ER homeostasis can be disrupted by the accumulation of misfolded proteins, resulting in ER stress, due to specific intra- or extracellular stresses. Processes including the unfolded protein response (UPR), ER-associated degradation (ERAD) and autophagy are thought to play important roles in restoring ER homeostasis. Here, we focus on summarizing and analysing recent advances in our understanding of the role of ERAD in plant physiological processes, especially in plant adaption to biotic and abiotic stresses, and also identify several issues that still need to be resolved in this field.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Plants; Unfolded Protein Response
PubMed: 31838748
DOI: 10.1111/nph.16369