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BioEssays : News and Reviews in... Feb 2021Autophagy functions in both selective and non-selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER-phagy) is a subclass of autophagy...
Autophagy functions in both selective and non-selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER-phagy) is a subclass of autophagy responsible for the degradation of the endoplasmic reticulum through selective encapsulation into autophagosomes. ER-phagy occurs both under physiological conditions and in response to stress cues, and plays a crucial role in maintaining the homeostatic control of the organelle. Although specific receptors that target parts of the ER membrane, as well as, internal proteins for lysosomal degradation have been identified, the molecular regulation of ER-phagy has been elusive. Recent work has uncovered novel regulators of ER-phagy that involve post-translational modifications of ER-resident proteins and functional cross-talk with other cellular processes. Herein, we discuss how morphology affects the function of the peripheral ER, and how ER-phagy modulates the turnover of this organelle. We also address how ER-phagy is regulated at the molecular level, considering implications relevant to human diseases.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Membrane Proteins; Protein Processing, Post-Translational
PubMed: 33210303
DOI: 10.1002/bies.202000212 -
The Journal of Physiology Jun 2016Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below... (Review)
Review
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are contact sites between the ER and the PM; the distance between the two organelles in the junctions is below 40 nm and the membranes are connected by protein tethers. A number of molecular tools and technical approaches have been recently developed to visualise, modify and characterise properties of ER-PM junctions. The junctions serve as the platforms for lipid exchange between the organelles and for cell signalling, notably Ca(2+) and cAMP signalling. Vice versa, signalling events regulate the development and properties of the junctions. Two Ca(2+) -dependent mechanisms of de novo formation of ER-PM junctions have been recently described and characterised. The junction-forming proteins and lipids are currently the focus of vigorous investigation. Junctions can be relatively short-lived and simple structures, forming and dissolving on the time scale of a few minutes. However, complex, sophisticated and multifunctional ER-PM junctions, capable of attracting numerous protein residents and other cellular organelles, have been described in some cell types. The road from simplicity to complexity, i.e. the transformation from simple 'nascent' ER-PM junctions to advanced stable multiorganellar complexes, is likely to become an attractive research avenue for current and future junctologists. Another area of considerable research interest is the downstream cellular processes that can be activated by specific local signalling events in the ER-PM junctions. Studies of the cell physiology and indeed pathophysiology of ER-PM junctions have already produced some surprising discoveries, likely to expand with advances in our understanding of these remarkable organellar contact sites.
Topics: Animals; Cell Membrane; Endoplasmic Reticulum; Humans; Intercellular Junctions
PubMed: 26939537
DOI: 10.1113/JP271142 -
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 -
Cold Spring Harbor Perspectives in... Apr 2023The Endoplasmic Reticulum (ER) is an endomembrane system that plays a multiplicity of roles in cell physiology and populates even the most distal cell compartments,... (Review)
Review
The Endoplasmic Reticulum (ER) is an endomembrane system that plays a multiplicity of roles in cell physiology and populates even the most distal cell compartments, including dendritic tips and axon terminals of neurons. Some of its functions are achieved by a cross talk with other intracellular membranous organelles and with the plasma membrane at membrane contacts sites (MCSs). As the ER synthesizes most membrane lipids, lipid exchanges mediated by lipid transfer proteins at MCSs are a particularly important aspect of this cross talk, which synergizes with the cross talk mediated by vesicular transport. Several mutations of genes that encode proteins localized at ER MCSs result in familial neurodegenerative diseases, emphasizing the importance of the normal lipid traffic within cells for a healthy brain. Here, we provide an overview of such diseases, with a specific focus on proteins that directly or indirectly impact lipid transport.
Topics: Endoplasmic Reticulum; Biological Transport; Cell Membrane; Lipids; Lipid Metabolism
PubMed: 36123033
DOI: 10.1101/cshperspect.a041257 -
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 -
FEBS Letters Sep 2019The synthesis, quality control, and trafficking of a third of the eukaryotic proteome takes place at the endoplasmic reticulum (ER), which is the largest cellular... (Review)
Review
The synthesis, quality control, and trafficking of a third of the eukaryotic proteome takes place at the endoplasmic reticulum (ER), which is the largest cellular organelle. Thus, biosynthetic trafficking from the ER, although constitutive, has to be tightly controlled. Increasing evidence indicates that the ER acts as a platform that initiates signaling events. In this review, we focus on signaling pathways that target components of the ER export machinery to regulate protein export. In addition, we discuss how signaling generated at the ER regulates various homeostatic cellular processes such as cell growth and proliferation, and how the deregulation thereof is involved in disease.
Topics: Animals; Endoplasmic Reticulum; Humans; Mutation; Signal Transduction
PubMed: 31381144
DOI: 10.1002/1873-3468.13569 -
DNA and Cell Biology Jun 2023The problems associated with economic development and social progress have led to an increase in the occurrence of cardiovascular diseases (CVDs), which affect the... (Review)
Review
The problems associated with economic development and social progress have led to an increase in the occurrence of cardiovascular diseases (CVDs), which affect the health of an increasing number of people and are a leading cause of disease and population mortality worldwide. Endoplasmic reticulum stress (ERS), a hot topic of interest for scholars in recent years, has been confirmed in numerous studies to be an important pathogenetic basis for many metabolic diseases and play an important role in maintaining physiological processes. The endoplasmic reticulum (ER) is a major organelle that is involved in protein folding and modification synthesis, and ERS occurs when several physiological and pathological factors allow excessive amounts of unfolded/misfolded proteins to accumulate. ERS often leads to initiation of the unfolded protein response (UPR) in a bid to re-establish tissue homeostasis; however, UPR has been documented to induce vascular remodeling and cardiomyocyte damage under various pathological conditions, leading to or accelerating the development of CVDs such as hypertension, atherosclerosis, and heart failure. In this review, we summarize the latest knowledge gained concerning ERS in terms of cardiovascular system pathophysiology, and discuss the feasibility of targeting ERS as a novel therapeutic target for the treatment of CVDs. Investigation of ERS has immense potential as a new direction for future research involving lifestyle intervention, the use of existing drugs, and the development of novel drugs that target and inhibit ERS.
Topics: Humans; Cardiovascular Diseases; Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Heart Failure
PubMed: 37140435
DOI: 10.1089/dna.2022.0532 -
Frontiers in Immunology 2022Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their... (Review)
Review
Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their communication neurotransmitters and neuropeptides depends on a high protein and lipid turnover. The endoplasmic Reticulum (ER) is fundamental to provide these necessary requirements for optimal neuronal function. Accumulation of misfolded proteins in the ER lumen, reactive oxygen species and exogenous stimulants like infections, chemical irritants and mechanical harm can induce ER stress, often followed by an ER stress response to reinstate cellular homeostasis. Imbedded between glial-, endothelial-, stromal-, and immune cells neurons are constantly in communication and influenced by their local environment. In this review, we discuss concepts of tissue homeostasis and innate immunity in the central and peripheral nervous system with a focus on its influence on ER stress, the unfolded protein response, and implications for health and disease.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Neurons; Unfolded Protein Response
PubMed: 35572517
DOI: 10.3389/fimmu.2022.859703 -
Biochemical Society Transactions Jun 2018The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and... (Review)
Review
The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and detoxification of endogenous and exogenous products. Its volume (and activity) must be maintained under normal growth conditions, must be expanded in a controlled manner on activation of ER stress programs and must be reduced to pre-stress size during the recovery phase that follows ER stress termination. ER-phagy is the constitutive or regulated fragmentation and delivery of ER fragments to lysosomal compartments for clearance. It gives essential contribution to the maintenance of cellular homeostasis, proteostasis, lipidostasis and oligosaccharidostasis (i.e. the capacity to produce the proteome, lipidome and oligosaccharidome in appropriate quality and quantity). ER turnover is activated on ER stress, nutrient deprivation, accumulation of misfolded polypeptides, pathogen attack and by activators of macroautophagy. The selectivity of these poorly characterized catabolic pathways is ensured by proteins displayed at the limiting membrane of the ER subdomain to be removed from cells. These proteins are defined as ER-phagy receptors and engage the cytosolic macroautophagy machinery via specific modules that associate with ubiquitin-like, cytosolic proteins of the Atg8/LC3/GABARAP family. In this review, we give an overview on selective ER turnover and on the yeast and mammalian ER-phagy receptors identified so far.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis
PubMed: 29802216
DOI: 10.1042/BST20170354