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Annual Review of Pathology 2015Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the... (Review)
Review
Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle--a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress-associated pathologies.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Unfolded Protein Response
PubMed: 25387057
DOI: 10.1146/annurev-pathol-012513-104649 -
EMBO Reports Aug 2022Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to... (Review)
Review
Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to this organelle control by degrading the excess or defective portions of organelles. The endoplasmic reticulum (ER) is an organelle with distinct structural domains associated with specific functions. The ER dynamically changes its mass, components, and shape in response to metabolic, developmental, or proteotoxic cues to maintain or regulate its functions. Therefore, elaborate mechanisms are required for proper degradation of the ER. Here, we review our current knowledge on diverse mechanisms underlying selective autophagy of the ER, which enable efficient degradation of specific ER subdomains according to different demands of cells.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Macroautophagy
PubMed: 35758175
DOI: 10.15252/embr.202255192 -
Cellular and Molecular Life Sciences :... Jan 2016The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The... (Review)
Review
The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
Topics: Animals; Calcium; Endoplasmic Reticulum; Fertilization; Humans; Lipid Metabolism; Mitosis; Protein Biosynthesis; Protein Folding; Proteins; Signal Transduction; Unfolded Protein Response
PubMed: 26433683
DOI: 10.1007/s00018-015-2052-6 -
Nature Jan 2016In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or... (Review)
Review
In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle, the accumulation of misfolded or unfolded proteins - known as endoplasmic reticulum stress - and the activation of the adaptive unfolded protein response to restore homeostasis. If protein misfolding is not resolved, cells die. Endoplasmic reticulum stress and activation of the unfolded protein response help to determine cell fate and function. Furthermore, endoplasmic reticulum stress contributes to the aetiology of many human diseases.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Molecular Targeted Therapy; Protein Folding; Proteins; Unfolded Protein Response
PubMed: 26791723
DOI: 10.1038/nature17041 -
The FEBS Journal Jan 2019The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production... (Review)
Review
The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Signal Transduction; Unfolded Protein Response
PubMed: 30027602
DOI: 10.1111/febs.14608 -
Nature Reviews. Molecular Cell Biology Jul 2007The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways -... (Review)
Review
The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
Topics: Animals; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Models, Biological; Oxidative Stress; Protein Folding; Signal Transduction
PubMed: 17565364
DOI: 10.1038/nrm2199 -
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 FEBS Journal Jan 2019The Endoplasmic Reticulum (ER) is the major site for secretory protein production in eukaryotic cells and like an efficient factory, it has the capacity to expand or... (Review)
Review
The Endoplasmic Reticulum (ER) is the major site for secretory protein production in eukaryotic cells and like an efficient factory, it has the capacity to expand or contract its output depending on the demand for its services. A primary function of the ER is to co-ordinate the quality control of proteins as they enter this folding factory at the base of the secretory pathway. Reduction-oxidation (redox) reactions have an important role to play in the quality control process, through the provision of disulphide bonds and by maintaining a favourable redox environment for oxidative protein folding. The ER is also a major contributor to calcium homeostasis and is a key site for lipid biosynthesis, two processes that additionally impact upon, and are influenced by, redox in the ER compartment.
Topics: Animals; Calcium; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Oxidation-Reduction; Signal Transduction; Unfolded Protein Response
PubMed: 30062765
DOI: 10.1111/febs.14618 -
The FEBS Journal Jan 2019This Special Issue comprises eleven excellent reviews that illustrate the role of ER stress in different human diseases, including myopathies and lung diseases, as well... (Review)
Review
This Special Issue comprises eleven excellent reviews that illustrate the role of ER stress in different human diseases, including myopathies and lung diseases, as well as in modulating liver dysfunction and inflammatory responses. These reviews also highlight the function of the UPR in neurodegenerative disorders and cancer, while discussing the potential benefits of targeting the UPR as a therapeutic approach. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Muscular Diseases; Neurodegenerative Diseases; Unfolded Protein Response
PubMed: 30677245
DOI: 10.1111/febs.14740 -
American Journal of Physiology. Cell... Feb 2017The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins,... (Review)
Review
The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins, inositol-requiring enzyme 1α, PRK-like ER kinase, and activating transcription factor 6, that monitor the protein-folding status of the ER and initiate corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins, conditions often encountered by cancer cells, can lead to the accumulation of misfolded proteins in the ER and cause "ER stress." Under remediable levels of ER stress, the homeostatic UPR outputs activate transcriptional and translational changes that promote cellular adaptation. However, if the ER stress is irreversible despite these measures, a terminal UPR program supersedes that actively signals cell destruction. In addition to its prosurvival and prodeath outputs, the UPR is now recognized to play a major role in the differentiation and activation of specific immune cells, as well as proinflammatory cytokine production in many cell types. Given the numerous intrinsic and extrinsic factors that threaten the fidelity of the secretory pathway in cancer cells, it is not surprising that ER stress is documented in many solid and hematopoietic malignancies, but whether ongoing UPR signaling is beneficial or detrimental to tumor growth remains hotly debated. Here I review recent evidence that cancer cells are prone to loss of proteostasis within the ER, and hence may be susceptible to targeted interventions that either reduce homeostatic UPR outputs or alternatively trigger the terminal UPR.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Models, Biological; Neoplasm Proteins; Neoplasms; Proteostasis Deficiencies; Unfolded Protein Response
PubMed: 27856431
DOI: 10.1152/ajpcell.00266.2016