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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 -
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 -
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 -
International Journal of Molecular... Dec 2022Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments,... (Review)
Review
Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Signal Transduction; Cell Death; Molecular Chaperones
PubMed: 36499512
DOI: 10.3390/ijms232315186 -
Cells May 2022Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein... (Review)
Review
Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca pool in cardiomyocytes are critical for the maintenance of proper cardiac function.
Topics: Calcium; Calreticulin; Endoplasmic Reticulum; Myocytes, Cardiac; Sarcoplasmic Reticulum
PubMed: 35681417
DOI: 10.3390/cells11111722 -
Experimental Diabetes Research 2012
Topics: Diabetes Complications; Diabetes Mellitus; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Mitochondria
PubMed: 22474432
DOI: 10.1155/2012/985075 -
Pulmonary Circulation 2020Pulmonary hypertension is a fatal disease of which pulmonary vasculopathy is the main pathological feature resulting in the mean pulmonary arterial pressure higher than... (Review)
Review
Pulmonary hypertension is a fatal disease of which pulmonary vasculopathy is the main pathological feature resulting in the mean pulmonary arterial pressure higher than 25 mmHg. Moreover, pulmonary hypertension remains a tough problem with unclear molecular mechanisms. There have been dozens of studies about endoplasmic reticulum stress during the onset of pulmonary hypertension in patients, suggesting that endoplasmic reticulum stress may have a critical effect on the pathogenesis of pulmonary hypertension. The review aims to summarize the rationale to elucidate the role of endoplasmic reticulum stress in pulmonary hypertension. Started by reviewing the mechanisms responsible for the unfolded protein response following endoplasmic reticulum stress, the potential link between endoplasmic reticulum stress and pulmonary hypertension were introduced, and the contributions of endoplasmic reticulum stress to different vascular cells, mitochondria, and inflammation were described, and finally the potential therapies of attenuating endoplasmic reticulum stress for pulmonary hypertension were discussed.
PubMed: 32110387
DOI: 10.1177/2045894019900121 -
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 -
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 -
Neural Regeneration Research Mar 2024Ferroptosis is a form of non-apoptotic programmed cell death, and its mechanisms mainly involve the accumulation of lipid peroxides, imbalance in the amino acid... (Review)
Review
Ferroptosis is a form of non-apoptotic programmed cell death, and its mechanisms mainly involve the accumulation of lipid peroxides, imbalance in the amino acid antioxidant system, and disordered iron metabolism. The primary organelle responsible for coordinating external challenges and internal cell demands is the endoplasmic reticulum, and the progression of inflammatory diseases can trigger endoplasmic reticulum stress. Evidence has suggested that ferroptosis may share pathways or interact with endoplasmic reticulum stress in many diseases and plays a role in cell survival. Ferroptosis and endoplasmic reticulum stress may occur after ischemic stroke. However, there are few reports on the interactions of ferroptosis and endoplasmic reticulum stress with ischemic stroke. This review summarized the recent research on the relationships between ferroptosis and endoplasmic reticulum stress and ischemic stroke, aiming to provide a reference for developing treatments for ischemic stroke.
PubMed: 37721292
DOI: 10.4103/1673-5374.380870