Secretory and membrane proteins are synthesized in ribosomes, then mature in the endoplasmic reticulum (ER), but if ER function is impaired, immature defective proteins accumulate in the ER. This ...situation is called ER stress: in response, a defensive mechanism called the unfolded protein response (UPR) is activated in cells to reduce the defective proteins. During the UPR, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and RNA-dependent protein kinase (PKR)-like ER kinase (PERK) are activated, stress signals are transduced to the outside of the ER, and various cell responses, including gene induction, occur. In ER-associated degradation (ERAD), one type of UPR, defective proteins are eventually expelled from the ER and degraded in the cytoplasm through the ubiquitin proteasome system. Since ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer, it is the focus of increased attention from the perspectives of elucidating pathogenic mechanisms, and in the development of therapeutics.
The function of the endoplasmic reticulum (ER) can be impaired by changes to the extra- and intracellular environment, such as disruption of calcium homeostasis, expression of mutated proteins, and ...oxidative stress. In response to disruptions to ER homeostasis, eukaryotic cells activate canonical branches of signal transduction cascades, collectively termed the unfolded protein response (UPR). The UPR functions to remove or recover the activity of misfolded proteins that accumulated in the ER and to avoid irreversible cellular damage. Additionally, the UPR plays unique physiological roles in the regulation of diverse cellular events, including cell differentiation and development and lipid biosynthesis. Recent studies have shown that these important cellular events are also regulated by contact and communication among organelles. These reports suggest strong involvement among the UPR, organelle communication, and regulation of cellular homeostasis. However, the precise mechanisms for the formation of contact sites and the regulation of ER dynamics by the UPR remain unresolved. In this review, we summarize the current understanding of how the UPR regulates morphological changes to the ER and the formation of contact sites between the ER and other organelles. We also review how UPR-dependent connections between the ER and other organelles affect cellular and physiological functions.
The COVID-19 pandemic has created urgent demand for rapid detection of the SARS-CoV-2 coronavirus. Herein, we report highly sensitive detection of SARS-CoV-2 nucleocapsid protein (N protein) using ...nanoparticle-enhanced surface plasmon resonance (SPR) techniques. A crucial plasmonic role in significantly enhancing the limit of detection (LOD) is revealed for exceptionally large gold nanoparticles (AuNPs) with diameters of hundreds of nm. SPR enhanced by these large nanoparticles lowered the LOD of SARS-CoV-2 N protein to 85 fM, resulting in the highest SPR detection sensitivity ever obtained for SARS-CoV-2 N protein.
MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non–small cell lung cancer. ...MET contains 11 potential N‐glycosylation sites, but the site‐specific roles of these N‐glycans have not been elucidated. We report herein that these N‐glycans regulate the proteolytic processing of MET and HGF‐induced MET signaling, and that this regulation is site specific. Inhibitors of N‐glycosylation were found to suppress the processing and trafficking of endogenous MET in H1975 and EBC‐1 lung cancer cells and exogenous MET in CHO‐K1 cells. We purified the recombinant extracellular domain of human MET and determined the site‐specific N‐glycan structures and occupancy using mass spectrometry. The results indicated that most sites were fully glycosylated and that the dominant population was the complex type. To examine the effects of the deletion of N‐glycans of MET, we prepared endogenous MET knockout Flp‐In CHO cells and transfected them with a series of N‐glycan–deletion mutants of MET. The results showed that several N‐glycans are implicated in the processing of MET. The findings also suggested that the N‐glycans of the SEMA domain of MET positively regulate HGF signaling, and the N‐glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing, cell surface expression, and signaling were significantly suppressed in the case of the all‐N‐glycan–deletion mutant. The overall findings suggest that N‐glycans of MET affect the status and the function of the receptor in a site‐specific manner.
N‐glycans of the SEMA domain of MET positively regulate hepatocyte growth factor (HGF) signaling, and the N‐glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing and signaling were significantly suppressed in the case of the all‐N‐glycan–deletion mutant. The overall findings suggest that N‐glycans of MET affect the status and the function of the receptor in a site‐specific manner.
The endoplasmic reticulum (ER) plays a pivotal role in maintaining cellular homeostasis. However, numerous environmental and genetic factors give rise to ER stress by inducing an accumulation of ...unfolded proteins. Under ER stress conditions, cells initiate the unfolded protein response (UPR). Here, we demonstrate a novel aspect of the UPR by electron microscopy and immunostaining analyses, whereby multivesicular body (MVB) formation was enhanced after ER stress. This MVB formation was influenced by inhibition of ER stress transducers inositol required enzyme 1 (IRE1) and PKR-like ER kinase (PERK). Furthermore, exosome release was also increased during ER stress. However, in IRE1 or PERK deficient cells, exosome release was not upregulated, indicating that IRE1- and PERK-mediated pathways are involved in ER stress-dependent exosome release.
•Endoplasmic reticulum (ER) stress induces multivesicular body (MVB) formation.•ER stress transducers IRE1 and PERK mediate MVB formation.•Exosome release is enhanced after ER stress.•IRE1 or PERK deficiency blocks upregulation of ER stress-dependent exosome release.
The nuclear envelope (NE) separates genomic DNA from the cytoplasm and provides the molecular platforms for nucleocytoplasmic transport, higher-order chromatin organization, and physical links ...between the nucleus and cytoskeleton. Recent studies have shown that the NE is often damaged by various stresses termed “NE stress”, leading to critical cellular dysfunction. Accumulating evidence has revealed the crucial roles of NE stress in the pathology of a broad spectrum of diseases. In the central nervous system (CNS), NE dysfunction impairs neural development and is associated with several neurological disorders, such as Alzheimer’s disease and autosomal dominant leukodystrophy. In this review, the structure and functions of the NE are summarized, and the concepts of NE stress and NE stress responses are introduced. Additionally, the significant roles of the NE in the development of CNS and the mechanistic connections between NE stress and neurological disorders are described.
Eukaryotic cells can adapt to endoplasmic reticulum (ER) dysfunction by producing diverse signals from the ER to the cytosol or nucleus. These signaling pathways are collectively known as the ...unfolded protein response (UPR). The canonical branches of the UPR are mediated by three ER membrane-bound proteins: double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). These ER stress transducers basically play important roles in cell survival after ER stress. Recently, novel types of ER stress transducers that share a region of high sequence similarity with ATF6 have been identified. They have a transmembrane domain, which allows them to associate with the ER, and possess a transcription-activation domain and a basic leucine zipper (bZIP) domain. These membrane-bound bZIP transcription factors include OASIS, BBF2H7 CREBH, CREB4 and Luman, and are collectively referred to as OASIS family members. Despite their structural similarities with ATF6, differences in activating stimuli and tissue distribution indicate specialized functions of each member on regulating UPR signaling in specific organs and tissues. One of them, OASIS, is expressed preferentially in astrocytes in the central nervous system (CNS). OASIS temporally regulates the differentiation from neural precursor cells into astrocytes to promote the expression of Glial Cell Missing 1 through dynamic interactions among OASIS family members followed by accelerating demethylation of the
Gfap
promoter. This review is a summary of our current understanding of the physiological functions of OASIS in the CNS.
This study aimed to investigate the effect of footsteps of a neighboring runner (NR) on the main runner's step frequency (SF), heart rate (HR), and rating of perceived exertion (RPE). The ...participants were male long-distance runners belonging to a university track and field team. Two experiments were conducted in which the main runner (participant) and NR (examiner) ran with the same running speed on two adjacent treadmills separated by a thin wall. The participants were instructed that the experimental purpose was to investigate the HR when running with others and running alone. In Experiment 1, NR performed three trials of changing the footstep tempo in 5 bpm (beat per minute) faster (+5bpmFS), 5 bpm slower (-5bpmFS), or no footsteps (NF) conditions. The results showed that the footstep condition affected the variability of the SF but not the mean SF. Next, Experiment 2 was conducted by increasing the footstep tempo condition. NR performed seven trials of changing the footstep tempo by ±3 bpm, ±5 bpm, ±10 bpm, or no footstep. The results showed that the footstep condition affected the mean SF and the SF decreased at -10bpmFS compared to NF. There were no differences in the HR and RPE between conditions. These results indicated that the footsteps of NR could influence the SF, although it was unclear whether footsteps were involved in the synchronization between runners. Overall, our findings emphasize the environmental factors that influence running behavior, including the NR's footsteps.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The protein folding capabilities in the endoplasmic reticulum (ER) are disturbed by alternations in the cellular homeostasis such as the disruption of calcium ion homeostasis, the expression of ...mutated proteins and oxidative stress. In response to these ER dysfunctions, eukaryotic cells activate canonical branches of signal transduction cascades to restore the protein folding capacity and avoid irreversible damages, collectively termed the unfolded protein response (UPR). Prolonged ER dysfunctions and the downregulation of UPR signaling pathways have been accepted as a crucial trigger for the pathogenesis of various neurodegenerative diseases. Furthermore, recent studies have revealed that the UPR has a wide spectrum of signaling pathways for unique physiological roles in the diverse developmental, differential and lipidomic processes. A developed and intricate ER network exists in the neurites of neurons. Neuronal ER functions and ER-derived signaling mediate efficient communication between cell soma and distal sites through local protein synthesis, sorting and lipogenesis. However, relevant of ER-derived UPR signaling pathways in the elaborate mechanisms regulating neuronal activities, synaptic functions and protective responses against injury is not fully elucidated. In this review, we summarized our current understanding of how the UPR functions provide the appropriate signals for neuronal capabilities. We also reviewed how UPR dysfunctions lead to the pathogenesis of neurodegenerative diseases, and the possibilities ameliorating their toxic effects by targeting UPR components.
•UPR signaling is activated in response to neuronal activities.•UPR signaling manipulates machineries of axons and dendrites.•Disturbance of UPR signaling leads to neurodegenerative diseases.
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