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Current Opinion in Cell Biology Aug 2023Phosphatidylserine (PS) is a negatively charged glycerophospholipid found mainly in the plasma membrane (PM) and in the late secretory/endocytic compartments, where it... (Review)
Review
Phosphatidylserine (PS) is a negatively charged glycerophospholipid found mainly in the plasma membrane (PM) and in the late secretory/endocytic compartments, where it regulates cellular activity and can mediate apoptosis. Export of PS from the endoplasmic reticulum, its site of synthesis, to other compartments, and its transbilayer asymmetry must therefore be precisely regulated. We review recent findings on nonvesicular transport of PS by lipid transfer proteins (LTPs) at membrane contact sites, on PS flip-flop between membrane leaflets by flippases and scramblases, and on PS nanoclustering at the PM. We also discuss emerging data on cooperation between scramblases and LTPs, how perturbation of PS distribution can lead to disease, and the specific role of PS in viral infection.
Topics: Phosphatidylserines; Cell Membrane; Biological Transport; Endoplasmic Reticulum; Mitochondrial Membranes
PubMed: 37413778
DOI: 10.1016/j.ceb.2023.102192 -
Cell Reports Aug 2023Coat protein complex I (COPI) is best known for its role in Golgi-endoplasmic reticulum (ER) trafficking, responsible for the retrograde transport of ER-resident...
Coat protein complex I (COPI) is best known for its role in Golgi-endoplasmic reticulum (ER) trafficking, responsible for the retrograde transport of ER-resident proteins. The ER is crucial to neuronal function, regulating Ca homeostasis and the distribution and function of other organelles such as endosomes, peroxisomes, and mitochondria via functional contact sites. Here we demonstrate that disruption of COPI results in mitochondrial dysfunction in Drosophila axons and human cells. The ER network is also disrupted, and the neurons undergo rapid degeneration. We demonstrate that mitochondria-ER contact sites (MERCS) are decreased in COPI-deficient axons, leading to Ca dysregulation, heightened mitophagy, and a decrease in respiratory capacity. Reintroducing MERCS is sufficient to rescue not only mitochondrial distribution and Ca uptake but also ER morphology, dramatically delaying neurodegeneration. This work demonstrates an important role for COPI-mediated trafficking in MERC formation, which is an essential process for maintaining axonal integrity.
Topics: Humans; Endoplasmic Reticulum; Coat Protein Complex I; Golgi Apparatus; Mitochondria; Axons
PubMed: 37498742
DOI: 10.1016/j.celrep.2023.112883 -
ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.EMBO Reports Aug 2023Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via...
Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.
Topics: tau Proteins; Mitochondria; Endoplasmic Reticulum; Protein Tyrosine Phosphatases; Cholesterol
PubMed: 37401859
DOI: 10.15252/embr.202357499 -
Cancer Biology & Medicine Oct 2023The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification,... (Review)
Review
The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification, and folding and transport, as well as the regulation of lipid and steroid metabolism and Ca homeostasis. Hypoxia, nutrient deficiency, and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER, thus activating ER stress (ERS) and the unfolded protein response, and resulting in either restoration of cellular homeostasis or cell death. ERS plays a crucial role in cancer oncogenesis, progression, and response to therapies. This article reviews current studies relating ERS to ovarian cancer, the most lethal gynecologic malignancy among women globally, and discusses pharmacological agents and possible targets for therapeutic intervention.
Topics: Female; Humans; Endoplasmic Reticulum Stress; Unfolded Protein Response; Signal Transduction; Ovarian Neoplasms; Endoplasmic Reticulum; Tumor Microenvironment
PubMed: 37817482
DOI: 10.20892/j.issn.2095-3941.2023.0232 -
Wiley Interdisciplinary Reviews. RNA 2023Cells are exposed to various pathological stimulus within the cardiovascular system that challenge cells to adapt and survive. Several of these pathological stimulus... (Review)
Review
Cells are exposed to various pathological stimulus within the cardiovascular system that challenge cells to adapt and survive. Several of these pathological stimulus alter the normal function of the endoplasmic reticulum (ER), leading to the accumulation of unfolded and misfolded proteins, thus triggering the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. Downstream components of the UPR regulate transcription and translation reprogramming to ensure selective gene expression in response to pathological stimulus, including the expression of non-coding RNAs (ncRNAs). The ncRNAs play crucial roles in regulating transcription and translation, and their aberrant expression is associated with the development of cardiovascular disease (CVD). Notably, ncRNAs and ER stress can modulate each other and synergistically affect the development of CVD. Therefore, studying the interaction between ER stress and ncRNAs is necessary for effective prevention and treatment of CVD. In this review, we discuss the UPR signaling pathway and ncRNAs followed by the interplay regulation of ER stress and ncRNAs in CVD, which provides further insights into the understanding of the pathogenesis of CVD and therapeutic strategies. This article is categorized under: RNA in Disease and Development > RNA in Disease.
Topics: Humans; Cardiovascular Diseases; Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; RNA, Untranslated
PubMed: 36420580
DOI: 10.1002/wrna.1767 -
Nature Reviews. Immunology Sep 2023Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes... (Review)
Review
Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of 'endoplasmic reticulum stress' that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.
Topics: Humans; Unfolded Protein Response; Endoplasmic Reticulum Stress; Neoplasms; Immunity; Endoplasmic Reticulum
PubMed: 36755160
DOI: 10.1038/s41577-023-00838-0 -
Advances in Experimental Medicine and... 2024Poxvirus assembly has been an intriguing area of research for several decades. While advancements in experimental techniques continue to yield fresh insights, many... (Review)
Review
Poxvirus assembly has been an intriguing area of research for several decades. While advancements in experimental techniques continue to yield fresh insights, many questions are still unresolved. Large genome sizes of up to 380 kbp, asymmetrical structure, an exterior lipid bilayer, and a cytoplasmic life cycle are some notable characteristics of these viruses. Inside the particle are two lateral bodies and a protein wall-bound-biconcave core containing the viral nucleocapsid. The assembly progresses through five major stages-endoplasmic reticulum (ER) membrane alteration and rupture, crescent formation, immature virion formation, genome encapsidation, virion maturation and in a subset of viruses, additional envelopment of the virion prior to its dissemination. Several large dsDNA viruses have been shown to follow a comparable sequence of events. In this chapter, we recapitulate our understanding of the poxvirus morphogenesis process while reviewing the most recent advances in the field. We also briefly discuss how virion assembly aids in our knowledge of the evolutionary links between poxviruses and other Nucleocytoplasmic Large DNA Viruses (NCLDVs).
Topics: Poxviridae; Virus Assembly; Humans; Genome, Viral; Virion; Animals; Evolution, Molecular; Endoplasmic Reticulum
PubMed: 38801570
DOI: 10.1007/978-3-031-57165-7_3 -
Cell Death & Disease Jul 2023The endoplasmic reticulum (ER) plays important roles in biosynthetic and metabolic processes, including protein and lipid synthesis, Ca homeostasis regulation, and... (Review)
Review
The endoplasmic reticulum (ER) plays important roles in biosynthetic and metabolic processes, including protein and lipid synthesis, Ca homeostasis regulation, and subcellular organelle crosstalk. Dysregulation of ER homeostasis can cause toxic protein accumulation, lipid accumulation, and Ca homeostasis disturbance, leading to cell injury and even death. Accumulating evidence indicates that the dysregulation of ER homeostasis promotes the onset and progression of kidney diseases. However, maintaining ER homeostasis through unfolded protein response, ER-associated protein degradation, autophagy or ER-phagy, and crosstalk with other organelles may be potential therapeutic strategies for kidney disorders. In this review, we summarize the recent research progress on the relationship and molecular mechanisms of ER dysfunction in kidney pathologies. In addition, the endogenous protective strategies for ER homeostasis and their potential application for kidney diseases have been discussed.
Topics: Humans; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Unfolded Protein Response; Kidney Diseases; Autophagy; Homeostasis; Lipids
PubMed: 37500613
DOI: 10.1038/s41419-023-05905-x -
ACS Nano Jul 2023Artificial or synthetic organelles are a key challenge for bottom-up synthetic biology. So far, synthetic organelles have typically been based on spherical membrane... (Review)
Review
Artificial or synthetic organelles are a key challenge for bottom-up synthetic biology. So far, synthetic organelles have typically been based on spherical membrane compartments, used to spatially confine selected chemical reactions. In vivo, these compartments are often far from being spherical and can exhibit rather complex architectures. A particularly fascinating example is provided by the endoplasmic reticulum (ER), which extends throughout the whole cell by forming a continuous network of membrane nanotubes connected by three-way junctions. The nanotubes have a typical diameter of between 50 and 100 nm. In spite of much experimental progress, several fundamental aspects of the ER morphology remain elusive. A long-standing puzzle is the straight appearance of the tubules in the light microscope, which form irregular polygons with contact angles close to 120°. Another puzzling aspect is the nanoscopic shapes of the tubules and junctions, for which very different images have been obtained by electron microcopy and structured illumination microscopy. Furthermore, both the formation and maintenance of the reticular networks require GTP and GTP-hydrolyzing membrane proteins. In fact, the networks are destroyed by the fragmentation of nanotubes when the supply of GTP is interrupted. Here, it is argued that all of these puzzling observations are intimately related to each other and to the dimerization of two membrane proteins anchored to the same membrane. So far, the functional significance of this dimerization process remained elusive and, thus, seemed to waste a lot of GTP. However, this process can generate an effective membrane tension that stabilizes the irregular polygonal geometry of the reticular networks and prevents the fragmentation of their tubules, thereby maintaining the integrity of the ER. By incorporating the GTP-hydrolyzing membrane proteins into giant unilamellar vesicles, the effective membrane tension will become accessible to systematic experimental studies.
Topics: Endoplasmic Reticulum; Membrane Proteins; Microscopy; Guanosine Triphosphate
PubMed: 37377213
DOI: 10.1021/acsnano.3c01338 -
Genes and Immunity Dec 2023Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a proteolytic enzyme involved in adaptive immunity. The ERAP2 gene is highly polymorphic and encodes haplotypes that... (Review)
Review
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a proteolytic enzyme involved in adaptive immunity. The ERAP2 gene is highly polymorphic and encodes haplotypes that confer resistance against lethal infectious diseases, but also increase the risk for autoimmune disorders. Identifying how ERAP2 influences susceptibility to these traits requires an understanding of the selective pressures that shaped and maintained allelic variation throughout human evolution. Our review discusses the genetic regulation of haplotypes and diversity in naturally occurring ERAP2 allotypes in the global population. We outline how these ERAP2 haplotypes evolved during human history and highlight the presence of Neanderthal DNA sequences in ERAP2 of modern humans. Recent evidence suggests that human adaptation during the last ~10,000 years and historic pandemics left a significant mark on the ERAP2 gene that determines susceptibility to infectious and inflammatory diseases today.
Topics: Humans; Aminopeptidases; Autoimmune Diseases; Endoplasmic Reticulum; Haplotypes; Minor Histocompatibility Antigens; Evolution, Molecular; Adaptive Immunity
PubMed: 37925533
DOI: 10.1038/s41435-023-00225-8