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Biological & Pharmaceutical Bulletin 2020Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC)... (Review)
Review
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptide-processing enzyme, specifically emphasizing on its secretory form.
Topics: Aminopeptidases; Animals; Endoplasmic Reticulum; Humans
PubMed: 32009107
DOI: 10.1248/bpb.b19-00857 -
Psychiatria Polska Jun 2020Depression is an important health problem around the world. There are several effective methods for its treatment, but it is estimated that one-third of patients with... (Review)
Review
Depression is an important health problem around the world. There are several effective methods for its treatment, but it is estimated that one-third of patients with depression do not respond adequately to conventional antidepressants. There is, therefore, an urgent need to identify the biological mechanism of depression and the pharmacological action of antidepressants. The participation of broadly understood inflammatory factors in the etiology of depressive disorders no longer raises doubts. In recent years, a lot of attention has also been devoted to changes in the endoplasmic reticulum, suggesting that the so-called endoplasmic reticulum stress gives rise to many diseases. The endoplasmic reticulum stress is activated in response to the increasing amount of unfolded or improperly folded proteins in the ER. Research on the so-called endoplasmic reticulum stress inspire hope not only in the context of amore thorough understanding of the pathophysiology of diseases, but it can also be an inspiration to search for new, more effective drugs. This paper presents the connections between changes of the endoplasmic reticulum and inflammatory states and oxidative-reduction balance. Both the occurrence of inflammation and so-called oxidative stress have been confirmed in depressive disorders.
Topics: Animals; Depression; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Oxidative Stress; Unfolded Protein Response
PubMed: 33038883
DOI: 10.12740/PP/109130 -
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 -
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 -
Journal of the American Chemical Society Nov 2023Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead...
Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead to the accumulation of pathological aggregates, correlating with aging and neurodegenerative diseases. However, a broadly applicable methodology is not available for the targeted degradation of protein aggregates or organelles in mammalian cells. Herein, we developed a series of autophagy receptor-inspired targeting chimeras (AceTACs) that can induce the targeted degradation of aggregation-prone proteins and protein aggregates (e.g., huntingtin, TDP-43, and FUS mutants), as well as organelles (e.g., mitochondria, peroxisomes, and endoplasmic reticulum). These antibody-fusion-based AceTAC degraders were designed to mimic the function of autophagy receptors, simultaneously binding with the cellular targets and the LC3 proteins on the autophagosomal membrane, eventually transporting the target to the autophagy-lysosomal process for degradation. The AceTAC degradation system provides design principles for antibody-based degradation through autophagy, largely expanding the scope of intracellular targeted degradation technologies.
Topics: Animals; Protein Aggregates; Autophagy; Endoplasmic Reticulum; Lysosomes; Peroxisomes; Mammals
PubMed: 37748140
DOI: 10.1021/jacs.3c05199 -
Developmental Cell Oct 2023Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular...
Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular stresses, COPII proteins become targets of regulation to control the transport. Here, we show that the COPII outer coat proteins Sec31 and Sec13 are selectively sequestered into the biomolecular condensate of SCOTIN/SHISA-5, which interferes with COPII vesicle formation and inhibits ER-to-Golgi transport. SCOTIN is an ER transmembrane protein with a cytosolic intrinsically disordered region (IDR), which is required and essential for the formation of condensates. Upon IFN-γ stimulation, which is a cellular condition that induces SCOTIN expression and condensation, ER-to-Golgi transport was inhibited in a SCOTIN-dependent manner. Furthermore, cancer-associated mutations of SCOTIN perturb its ability to form condensates and control transport. Together, we propose that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.
Topics: Vesicular Transport Proteins; Biological Transport; Protein Transport; Endoplasmic Reticulum; Golgi Apparatus
PubMed: 37816329
DOI: 10.1016/j.devcel.2023.08.030 -
Frontiers in Immunology 2022Stimulator of interferon genes (STING) is an endoplasmic-reticulum resident protein, playing essential roles in immune responses against microbial infections. However,... (Review)
Review
Stimulator of interferon genes (STING) is an endoplasmic-reticulum resident protein, playing essential roles in immune responses against microbial infections. However, over-activation of STING is accompanied by excessive inflammation and results in various diseases, including autoinflammatory diseases and cancers. Therefore, precise regulation of STING activities is critical for adequate immune protection while limiting abnormal tissue damage. Numerous mechanisms regulate STING to maintain homeostasis, including protein-protein interaction and molecular modification. Among these, post-translational modifications (PTMs) are key to accurately orchestrating the activation and degradation of STING by temporarily changing the structure of STING. In this review, we focus on the emerging roles of PTMs that regulate activation and inhibition of STING, and provide insights into the roles of the PTMs of STING in disease pathogenesis and as potential targeted therapy.
Topics: Endoplasmic Reticulum; Humans; Immunity, Innate; Inflammation; Membrane Proteins; Protein Processing, Post-Translational
PubMed: 35603197
DOI: 10.3389/fimmu.2022.888147 -
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 -
Journal of Integrative Plant Biology Apr 2022A central role of the endoplasmic reticulum (ER) is the synthesis, folding and quality control of secretory proteins. Secretory proteins usually exit the ER to enter the... (Review)
Review
A central role of the endoplasmic reticulum (ER) is the synthesis, folding and quality control of secretory proteins. Secretory proteins usually exit the ER to enter the Golgi apparatus in coat protein complex II (COPII)-coated vesicles before transport to different subcellular destinations. However, in plants there are specialized ER-derived vesicles (ERDVs) that carry specific proteins but, unlike COPII vesicles, can exist as independent organelles or travel to the vacuole in a Golgi-independent manner. These specialized ERDVs include protein bodies and precursor-accumulating vesicles that accumulate storage proteins in the endosperm during seed development. Specialized ERDVs also include precursor protease vesicles that accumulate amino acid sequence KDEL-tailed cysteine proteases and ER bodies in Brassicales plants that accumulate myrosinases that hydrolyzes glucosinolates. These functionally specialized ERDVs act not only as storage organelles but also as platforms for signal-triggered processing, activation and deployment of specific proteins with important roles in plant growth, development and adaptive responses. Some specialized ERDVs have also been exploited to increase production of recombinant proteins and metabolites. Here we discuss our current understanding of the functional diversity, evolutionary mechanisms and biotechnological application of specialized ERDVs, which are associated with some of the highly remarkable characteristics important to plants.
Topics: COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Plants; Protein Transport
PubMed: 35142108
DOI: 10.1111/jipb.13233 -
FEBS Letters Sep 2022In eukaryotes, the endomembrane system allows for spatiotemporal compartmentation of complicated cellular processes. The plant endomembrane system consists of the... (Review)
Review
In eukaryotes, the endomembrane system allows for spatiotemporal compartmentation of complicated cellular processes. The plant endomembrane system consists of the endoplasmic reticulum, the Golgi apparatus, the trans-Golgi network, the multivesicular body and the vacuole. Anterograde traffic from the endoplasmic reticulum to the Golgi apparatus is mediated by coat protein complex II (COPII) vesicles. Autophagy, an evolutionarily conserved catabolic process that turns over cellular materials upon nutrient deprivation or in adverse environments, exploits double-membrane autophagosomes to recycle unwanted constituents in the lysosome/vacuole. Accumulating evidence reveals novel functions of plant COPII vesicles in autophagy and their regulation by abiotic stresses. Here, we summarize current knowledge about plant COPII vesicles in endomembrane trafficking and then highlight recent findings showing their distinct roles in modulating the autophagic flux and stress responses.
Topics: Autophagy; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Protein Transport
PubMed: 35486434
DOI: 10.1002/1873-3468.14362