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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 -
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 FEBS Journal Dec 2023Lysosomal degradation of the endoplasmic reticulum (ER) and its components through the autophagy pathway has emerged as a major regulator of ER proteostasis. Commonly... (Review)
Review
Lysosomal degradation of the endoplasmic reticulum (ER) and its components through the autophagy pathway has emerged as a major regulator of ER proteostasis. Commonly referred to as ER-phagy and ER-to-lysosome-associated degradation (ERLAD), how the ER is targeted to the lysosome has been recently clarified by a growing number of studies. Here, we summarize the discoveries of the molecular components required for lysosomal degradation of the ER and their proposed mechanisms of action. Additionally, we discuss how cells employ these machineries to create the different routes of ER-lysosome-associated degradation. Further, we review the role of ER-phagy in viral infection pathways, as well as the implication of ER-phagy in human disease. In sum, we provide a comprehensive overview of the current field of ER-phagy.
Topics: Humans; Secretome; Autophagy; Endoplasmic Reticulum-Associated Degradation; Lysosomes; Endoplasmic Reticulum; Endoplasmic Reticulum Stress
PubMed: 37920925
DOI: 10.1111/febs.16986 -
Oxidative Medicine and Cellular... 2022In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as... (Review)
Review
In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review discusses the molecular mechanism underlying ER stress and OS response as both causes and consequences of ischemic stroke. We also summarize the latest advances in understanding the importance of ER stress and OS in the pathogenesis of ischemic stroke and discuss potential strategies and clinical trials explicitly aiming to restore mitochondria and ER dynamics after IS.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Ischemic Stroke; Mitochondria; Signal Transduction
PubMed: 35528523
DOI: 10.1155/2022/3335887 -
Biomolecules Nov 2022The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER,... (Review)
Review
The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD.
Topics: Humans; Endoplasmic Reticulum Stress; Unfolded Protein Response; Autophagy; Endoplasmic Reticulum; Apoptosis; Pulmonary Disease, Chronic Obstructive
PubMed: 36358987
DOI: 10.3390/biom12111637 -
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 -
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