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International Journal of Molecular... Jan 2023Unfolded protein response (UPR) is an adaptive response which is used for re-establishing protein homeostasis, and it is triggered by endoplasmic reticulum (ER) stress.... (Review)
Review
Unfolded protein response (UPR) is an adaptive response which is used for re-establishing protein homeostasis, and it is triggered by endoplasmic reticulum (ER) stress. Specific ER proteins mediate UPR activation, after dissociation from chaperone Glucose-Regulated Protein 78 (GRP78). UPR can decrease ER stress, producing an ER adaptive response, block UPR if ER homeostasis is restored, or regulate apoptosis. Some tumour types are linked to ER protein folding machinery disturbance, highlighting how UPR plays a pivotal role in cancer cells to keep malignancy and drug resistance. In this review, we focus on some molecules that have been revealed to target ER stress demonstrating as UPR could be a new target in cancer treatment.
Topics: Humans; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum; Heat-Shock Proteins; Unfolded Protein Response; Endoplasmic Reticulum Stress; Neoplasms; Apoptosis
PubMed: 36675080
DOI: 10.3390/ijms24021566 -
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 -
Life Sciences Jun 2023The endoplasmic reticulum (ER) is a dynamic organelle and a reliable performer for precisely folded proteins. To maintain its function and integrity, arrays of sensory... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic organelle and a reliable performer for precisely folded proteins. To maintain its function and integrity, arrays of sensory and quality control systems enhance protein folding fidelity and resolve the highest error-prone areas. Yet numerous internal and external factors disrupt its homeostasis and trigger ER stress responses. Cells try to reduce the number of misfolded proteins via the UPR mechanism, and ER-related garbage disposals systems like ER-associated degradation (ERAD), ER-lysosome-associated degradation (ERLAD), ER-Associated RNA Silencing (ERAS), extracellular chaperoning, and autophagy systems, which activates and increase the cell survival rate by degrading misfolded proteins, prevent the aggregated proteins and remove the dysfunctional organelles. Throughout life, organisms must confront environmental stress to survive and develop. Communication between the ER & other organelles, signaling events mediated by calcium, reactive oxygen species, and inflammation are linked to diverse stress signaling pathways and regulate cell survival or cell death mechanisms. Unresolved cellular damages can cross the threshold limit of their survival, resulting in cell death or driving for various diseases. The multifaceted ability of unfolded protein response facilitates the therapeutic target and a biomarker for various diseases, helping with early diagnosis and detecting the severity of diseases.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum-Associated Degradation; Endoplasmic Reticulum; Molecular Chaperones
PubMed: 37075943
DOI: 10.1016/j.lfs.2023.121705 -
Journal of Investigative Medicine : the... Feb 2021The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for... (Review)
Review
The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Protein Folding; Signal Transduction; Unfolded Protein Response
PubMed: 33472886
DOI: 10.1136/jim-2020-001570 -
Frontiers in Cellular and Infection... 2022The endoplasmic reticulum (ER) of higher eukaryotic cells forms an intricate membranous network that serves as the main processing facility for folding and assembling of... (Review)
Review
The endoplasmic reticulum (ER) of higher eukaryotic cells forms an intricate membranous network that serves as the main processing facility for folding and assembling of secreted and membrane proteins. The ER is a highly dynamic organelle that interacts with other intracellular structures, as well as endosymbiotic pathogenic and non-pathogenic microorganisms. A strict ER quality control (ERQC) must work to ensure that proteins entering the ER are folded and processed correctly. Unfolded or misfolded proteins are usually identified, selected, and addressed to Endoplasmic Reticulum-Associated Degradation (ERAD) complex. Conversely, when there is a large demand for secreted proteins or ER imbalance, the accumulation of unfolded or misfolded proteins activates the Unfold Protein Response (UPR) to restore the ER homeostasis or, in the case of persistent ER stress, induces the cell death. Pathogenic trypanosomatids, such as , and are the etiological agents of important neglected diseases. These protozoans have a complex life cycle alternating between vertebrate and invertebrate hosts. The ER of trypanosomatids, like those found in higher eukaryotes, is also specialized for secretion, and depends on the ERAD and non-canonical UPR to deal with the ER stress. Here, we reviewed the basic aspects of ER biology, organization, and quality control in trypanosomatids. We also focused on the unusual way by which , , and spp. respond to ER stress, emphasizing how these parasites' ER-unrevealed roads might be an attractive target for chemotherapy.
Topics: Unfolded Protein Response; Endoplasmic Reticulum-Associated Degradation; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Proteins; Leishmania
PubMed: 36439218
DOI: 10.3389/fcimb.2022.1057774 -
Developmental Cell Apr 2021The endoplasmic reticulum (ER) is a ubiquitous organelle that is vital to the life of eukaryotic cells. It synthesizes essential lipids and proteins and initiates the... (Review)
Review
The endoplasmic reticulum (ER) is a ubiquitous organelle that is vital to the life of eukaryotic cells. It synthesizes essential lipids and proteins and initiates the glycosylation of intracellular and surface proteins. As such, the ER is necessary for cell growth and communication with the external environment. The ER is also a highly dynamic organelle, whose structure is continuously remodeled through an interaction with the cytoskeleton and the action of specialized ER shapers. Recent and significant advances in ER studies have brought to light conserved and unique features underlying the structure and function of this organelle in plant cells. In this review, exciting developments in the understanding of the mechanisms for plant ER structural and functional homeostasis, particularly those that underpin ER network architecture and ER degradation, are presented and discussed.
Topics: Cytoskeleton; Endoplasmic Reticulum; Homeostasis; Plants
PubMed: 33662257
DOI: 10.1016/j.devcel.2021.02.008 -
The Chinese Journal of Dental Research Jun 2021The endoplasmic reticulum has emerged as a modulator that is essential for cellular homeostasis and human health. It is an extensive membranous organelle that acts as a... (Review)
Review
The endoplasmic reticulum has emerged as a modulator that is essential for cellular homeostasis and human health. It is an extensive membranous organelle that acts as a hub for the physiological and pathological processes. In recent years, it has become a topic of interest in studies on the relationship between endoplasmic reticulum homeostasis and system diseases. Periodontal disease is a prevalent chronic disease that affects tooth-supporting tissues, initiated by the interaction between pathogenic bacterial infection and immune defence and resulting in tooth loss. The endoplasmic reticulum participates in the responses to the fluctuating microenvironments in periodontal pathogenesis and regulates periodontal homeostasis. In this review, we present an overview of the significance of endoplasmic reticulum regulation as a multidimensional mediator in periodontal disease and highlight the potential strategies for periodontal regeneration.
Topics: Endoplasmic Reticulum; Humans; Periodontal Diseases
PubMed: 34219440
DOI: 10.3290/j.cjdr.b1530481 -
Journal of Cellular Physiology Aug 2023Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney... (Review)
Review
Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria-ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria-associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.
Topics: Humans; Mitochondrial Dynamics; Epigenesis, Genetic; Endoplasmic Reticulum; Mitochondria; Kidney Diseases; Endoplasmic Reticulum Stress
PubMed: 37357431
DOI: 10.1002/jcp.31058 -
Cells Mar 2021The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or... (Review)
Review
The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or antagonize each other with regards to cell function. Crosstalk between organelles has become a significant topic in research over recent decades. We believe that signal transduction between organelles, especially the endoplasmic reticulum (ER) and mitochondria, is a factor that can influence the cell fate. As the cellular center for protein folding and modification, the endoplasmic reticulum can influence a range of physiological processes by regulating the quantity and quality of proteins. Mitochondria, as the cellular "energy factory," are also involved in cell death processes. Some researchers regard the ER as the sensor of cellular stress and the mitochondria as an important actuator of the stress response. The scientific community now believe that bidirectional communication between the ER and the mitochondria can influence cell death. Recent studies revealed that the death signals can shuttle between the two organelles. Mitochondria-associated membranes (MAMs) play a vital role in the complex crosstalk between the ER and mitochondria. MAMs are known to play an important role in lipid synthesis, the regulation of Ca homeostasis, the coordination of ER-mitochondrial function, and the transduction of death signals between the ER and the mitochondria. Clarifying the structure and function of MAMs will provide new concepts for studying the pathological mechanisms associated with neurodegenerative diseases, aging, and cancers. Here, we review the recent studies of the structure and function of MAMs and its roles involved in cell death, especially in apoptosis.
Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Calcium Signaling; Endoplasmic Reticulum; Energy Metabolism; Humans; Lipogenesis; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins
PubMed: 33809551
DOI: 10.3390/cells10030657 -
Cell Biology and Toxicology Dec 2022Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic... (Review)
Review
Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic toxicity. Recent studies indicate that the endoplasmic reticulum (ER) could play an important role in drug toxicity by participating in the metabolic activation of drugs and could be a primarily attacked target by reactive metabolites. In this article, we summarize the generation and mechanism of reactive metabolites in ER stress and their associated cell death and inflammatory cascade, as well as the systematic modulation of unfolded protein response (UPR)-mediated adaptive pathways.
Topics: Humans; Apoptosis; Unfolded Protein Response; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Drug-Related Side Effects and Adverse Reactions
PubMed: 35040016
DOI: 10.1007/s10565-021-09689-8