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Annual Review of Nutrition Jul 2016The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol,... (Review)
Review
The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum-associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.
Topics: Animals; Cholesterol; Endoplasmic Reticulum; Endoplasmic Reticulum-Associated Degradation; Gene Expression Regulation, Enzymologic; Homeostasis; Humans; Lipid Metabolism; Lipoproteins; Models, Biological; Protein Biosynthesis; Protein Folding; Protein Stability; Secretory Pathway; Triglycerides
PubMed: 27296502
DOI: 10.1146/annurev-nutr-071715-051030 -
International Journal of Molecular... May 2022Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of approximately 10,000 different soluble and membrane proteins of human cells,...
Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of approximately 10,000 different soluble and membrane proteins of human cells, which amounts to about 30% of the proteome [...].
Topics: Endoplasmic Reticulum; Humans; Membrane Proteins; Protein Transport
PubMed: 35628123
DOI: 10.3390/ijms23105315 -
Cancer Letters May 2019The endoplasmic reticulum (ER) is the primary organelle responsible for the synthesis, modification, folding and secretion of proteins, especially in specialized... (Review)
Review
The endoplasmic reticulum (ER) is the primary organelle responsible for the synthesis, modification, folding and secretion of proteins, especially in specialized secretory cells. It also contributes to the maintenance of cellular functions, such as Ca storage, lipogenesis, gluconeogenesis, and organelle biogenesis. Cellular stress conditions, such as glucose deprivation, hypoxia and disturbance of Ca homeostasis, may increase the risk of protein misfolding and perturb proteostasis. This activates ER stress and triggers the unfolded protein response (UPR), leading to either the restoration of homeostasis or cell death. ER stress and UPR have been shown to play crucial roles in the pathogenesis, progression and treatment response of various cancers. In gastric cancer (GC), one of the most aggressive cancer types, critical functions of ER stress signaling have also started to emerge. Herein, we summarize the current knowledge linking ER stress and UPR to GC; we also discuss the possible nodes of therapeutic intervention and propose directions of future research.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Proteostasis; Signal Transduction; Stomach Neoplasms; Unfolded Protein Response
PubMed: 30776479
DOI: 10.1016/j.canlet.2019.01.034 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jan 2021Endoplasmic reticulum (ER) is an important organelle where folding and post-translational modification of secretory and transmembrane proteins take place. During virus...
Endoplasmic reticulum (ER) is an important organelle where folding and post-translational modification of secretory and transmembrane proteins take place. During virus infection, cellular or viral unfolded and misfolded proteins accumulate in the ER in an event called ER stress. To maintain the equilibrium homeostasis of the ER, signal-transduction pathways, known as unfolded protein response (UPR), are activated. The viruses in turn manipulate UPR to maintain an environment favorable for virus survival and replication. Herpesviruses are enveloped DNA viruses that produce over 70 viral proteins. Modification and maturation of large quantities of viral glycosylated envelope proteins during virus replication may induce ER stress, while ER stress play both positive and negative roles in virus infection. Here we summarize the research progress of crosstalk between herpesvirus infection and the virus-induced ER stress.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Herpesviridae; Signal Transduction; Unfolded Protein Response
PubMed: 33501790
DOI: 10.13345/j.cjb.200226 -
The FEBS Journal Jan 2019Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type... (Review)
Review
Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response and/or the integrated stress response. Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress. Similarly, tissue hypoxia can lead to impaired protein homeostasis (proteostasis). But the mechanisms linking smoke and hypoxia to ER stress are only partially understood. In this review, we will examine the role of ER stress in the pathogenesis of lung disease by focusing on fibrosis, smoke, and hypoxia.
Topics: Animals; Asphyxia; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Hypoxia; Protein Folding; Pulmonary Fibrosis; Smoking; Unfolded Protein Response
PubMed: 29323786
DOI: 10.1111/febs.14381 -
Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases.Cells Sep 2021The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker... (Review)
Review
The endoplasmic reticulum (ER) is an organelle that is responsible for many essential subcellular processes. Interconnected narrow tubules at the periphery and thicker sheet-like regions in the perinuclear region are linked to the nuclear envelope. It is becoming apparent that the complex morphology and dynamics of the ER are linked to its function. Mutations in the proteins involved in regulating ER structure and movement are implicated in many diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). The ER is also hijacked by pathogens to promote their replication. Bacteria such as and as well as the Zika virus, bind to ER morphology and dynamics-regulating proteins to exploit the functions of the ER to their advantage. This review covers our understanding of ER morphology, including the functional subdomains and membrane contact sites that the organelle forms. We also focus on ER dynamics and the current efforts to quantify ER motion and discuss the diseases related to ER morphology and dynamics.
Topics: Animals; Cytoskeleton; Endoplasmic Reticulum; Humans; Lipids; Membrane Proteins; Microtubules; Mitochondria; Mitochondrial Membranes; Nuclear Envelope; Structure-Activity Relationship
PubMed: 34571990
DOI: 10.3390/cells10092341 -
American Journal of Physiology. Cell... Jan 2020The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of... (Review)
Review
The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 "interactome" and discuss the pathological and physiological role of such AGR2 interactions.
Topics: Animals; Endoplasmic Reticulum; Humans; Mucoproteins; Multiprotein Complexes; Oncogene Proteins; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction
PubMed: 31644305
DOI: 10.1152/ajpcell.00532.2018 -
Cold Spring Harbor Perspectives in... Jun 2011The endoplasmic reticulum (ER) as an intracellular Ca(2+) store not only sets up cytosolic Ca(2+) signals, but, among other functions, also assembles and folds newly... (Review)
Review
The endoplasmic reticulum (ER) as an intracellular Ca(2+) store not only sets up cytosolic Ca(2+) signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca(2+) depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca(2+) may no longer sustain essential cell functions. On the other hand, loss of luminal Ca(2+) causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca(2+) depletion.
Topics: Apoptosis; Calcium; Calcium Metabolism Disorders; Calcium Signaling; Endoplasmic Reticulum; Homeostasis; Humans; Models, Biological; Protein Folding
PubMed: 21441595
DOI: 10.1101/cshperspect.a004317 -
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 -
Virology May 2015Poxviruses differ from most DNA viruses by replicating entirely within the cytoplasm. The first discernible viral structures are crescents and spherical immature virions... (Review)
Review
Poxviruses differ from most DNA viruses by replicating entirely within the cytoplasm. The first discernible viral structures are crescents and spherical immature virions containing a single lipoprotein membrane bilayer with an external honeycomb lattice. Because this viral membrane displays no obvious continuity with a cellular organelle, a de novo origin was suggested. Nevertheless, transient connections between viral and cellular membranes could be difficult to resolve. Despite the absence of direct evidence, the intermediate compartment (ERGIC) between the endoplasmic reticulum (ER) and Golgi apparatus and the ER itself were considered possible sources of crescent membranes. A break-through in understanding poxvirus membrane biogenesis has come from recent studies of the abortive replication of several vaccinia virus null mutants. Novel images showing continuity between viral crescents and the ER and the accumulation of immature virions in the expanded ER lumen provide the first direct evidence for a cellular origin of this poxvirus membrane.
Topics: Animals; Endoplasmic Reticulum; Host-Pathogen Interactions; Humans; Intracellular Membranes; Poxviridae; Virus Assembly
PubMed: 25728299
DOI: 10.1016/j.virol.2015.02.003