bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒03‒07
twenty-one papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital


  1. Sheng Li Xue Bao. 2021 Feb 25. 73(1): 115-125
      In eukaryotic cells, the endoplasmic reticulum (ER) is the key quality control organelle for cellular protein synthesis and processing. It also serves as an important site for Ca2+ storage and lipid biosynthesis. In response to a variety of external stimuli, a cellular unfolded protein response (UPR) is activated to handle ER stress caused by increased accumulation of unfolded or misfolded proteins at the ER. The UPR plays a crucial role in maintaining ER homeostasis and cell functions. Three ER-localized transmembrane proteins, inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6), act to sense ER stress and mediate three canonical UPR signaling pathways. Besides restoring the protein folding capability to relieve ER stress, the UPR pathways have also been implicated in the regulation of cell metabolism and energy balance. In the state of overnutrition, ER stress has been documented to occur in adipose tissue that has a key role in energy storage and consumption. As an endocrine organ, adipose tissue regulates glucose and lipid metabolism through secreting adipocyte cytokines, and it undergoes metabolic inflammation during pathogenic development of obesity, insulin resistance and type 2 diabetes. In this review, we attempt to summarize the recent progress with regard to the UPR regulation of adipose tissue physiology. We wish to focus upon the mechanism by which ER stress response is linked to adipose tissue dysfunction, hoping to promote our current understanding of UPR signaling in the pathophysiology of obesity and related metabolic diseases.
  2. Biomolecules. 2021 Feb 26. pii: 354. [Epub ahead of print]11(3):
      With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer's disease (AD) and Parkinson's disease (PD), the less frequent Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.
    Keywords:  ALS; Alzheimer’s disease; ER stress; Huntington’s disease; Parkinson’s disease; eIF2; integrated stress response; unfolded protein response
    DOI:  https://doi.org/10.3390/biom11030354
  3. Cancer Discov. 2021 Mar 05.
      Double-strand breaks in mitochondrial DNA upregulated IFN signaling via cytosolic RNA sensing.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-031
  4. Expert Rev Mol Med. 2021 Mar 04. 23 e1
      Unfolded protein response (UPR) is an evolutionarily conserved pathway triggered during perturbation of endoplasmic reticulum (ER) homeostasis in response to the accumulation of unfolded/misfolded proteins under various stress conditions like viral infection, diseased states etc. It is an adaptive signalling cascade with the main purpose of relieving the stress from the ER, which may otherwise lead to the initiation of cell death via apoptosis. ER stress if prolonged, contribute to the aetiology of various diseases like cancer, type II diabetes, neurodegenerative diseases, viral infections etc. Understanding the role of UPR in disease progression will help design pharmacological drugs targeting the sensors of signalling cascade acting as potential therapeutic agents against various diseases. The current review aims at highlighting the relevance of different pathways of UPR in disease progression and control, including the available pharmaceutical interventions responsible for ameliorating diseased state via modulating UPR pathways.
    Keywords:  Cancer; ER stress; neurodegenerative diseases; therapeutic intervention; type II diabetes; unfolded protein response pathways; viral infection
    DOI:  https://doi.org/10.1017/erm.2021.2
  5. Nat Cell Biol. 2021 Mar 04.
      The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida-knockout mice. The PKA-AIDA-UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.
    DOI:  https://doi.org/10.1038/s41556-021-00642-9
  6. Aging (Albany NY). 2021 Feb 26. 13
      mTOR is well known to promote tumor growth but its roles in enhancing chemotherapy and radiotherapy have not been well studied. mTOR inhibition by rapamycin can sensitize cancer cells to radiotherapy. Here we show that Maf1 is required for rapamycin to increase radio-sensitivity in A549 lung cancer cells. In response to ionizing radiation (IR), Maf1 is inhibited by Akt-dependent re-phosphorylation, which activates mitochondrial unfolded protein response (UPRmt) through ATF5. Rapamycin suppresses IR-induced Maf1 re-phosphorylation and UPRmt activation in A549 cells, resulting in increased sensitivity to IR-mediated cytotoxicity. Consistently, Maf1 knockdown activates ATF5-transcription of mtHSP70 and HSP60, enhances mitochondrial membrane potential, reduces intracellular ROS levels and dampens rapamycin's effect on increasing IR-mediated cytotoxicity. In addition, Maf1 overexpression suppresses ethidium bromide-induced UPRmt and enhances IR-mediated cytotoxicity. Supporting our cell-based studies, elevated expression of UPRmt makers (mtHSP70 and HSP60) are associated with poor prognosis in patients with lung adenocarcinoma (LAUD). Together, our study reveals a novel role of Maf1-UPRmt axis in mediating rapamycin's enhancing effect on IR sensitivity in A549 lung cancer cells.
    Keywords:  Maf1; mTOR; mitochondrial unfolded protein response; non-small cell lung cancer cell; radio-resistance
    DOI:  https://doi.org/10.18632/aging.202584
  7. Oncol Lett. 2021 Apr;21(4): 252
      Glioma is the most common primary brain tumor and glioblastoma multiforme (GBM) is the most malignant brain glioma with the worst prognosis. T cell immune regulator 1 (TCIRG1) constitutes the V0a3 subunit of vacuolar ATPase (V-ATPase), and the function of V-ATPase in malignant tumors, such as breast cancer, melanoma and hepatocellular carcinoma, has been reported. However, the effect of the TCIRG1 subunit on GBM remains to be fully elucidated. mRNA levels of TCIRG1 in different cancer types and the corresponding normal tissues were extracted from the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The Gene Expression Omnibus (access number: GSE16011), the Chinese Glioma Genome Atlas and The Cancer Genome Atlas were used to investigate the mRNA level of TCIRG1 in glioma. Protein level validation in glioma was performed using western blotting. The Database for Annotation, Visualization and Integrated Discovery was used to analyze Gene Ontology (GO) categories for genes correlated with TCIRG1 in GBM. Protein-protein interaction (PPI) networks and module analyses were performed using Cytoscape software and the MCODE plugin. The correlation between tumor immune cell infiltration and TCIRG1 expression was explored using the TIMER database. Additionally, the correlation between TCIRG1 and the gene signature of immune infiltration was explored through TIMER and Gene Expression Profiling Interactive Analysis. External validation of TCIRG1 expression according to immune signatures in GBM was performed using the GSE16011 dataset with the GlioVis online tool. It was found that TCIRG1 expression was increased in GBM and numerous malignant tumors and may serve as a biomarker of the mesenchymal subtype of GBM. GO category analysis of positively correlated genes revealed that TCIRG1 was correlated with the immune response in GBM. PPI network and module analyses also supported the potential function of TCIRG1 in the local immune response. The expression of TCIRG1 was associated with various immune markers. It was therefore speculated that TCIRG1 is associated with glioma malignancy and may be a marker of unfavorable prognosis in patients with GBM, and it could be regarded as a prognostic biomarker and an indicator of immune infiltration in GBM.
    Keywords:  T cell immune regulator 1; glioblastoma multiforme; immune response; vacuolar ATPase
    DOI:  https://doi.org/10.3892/ol.2021.12514
  8. Nature. 2021 Mar 03.
      
    Keywords:  Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-021-00511-3
  9. Nature. 2021 Mar 03.
      
    Keywords:  Computer science; Information technology; Molecular biology; Synthetic biology
    DOI:  https://doi.org/10.1038/d41586-021-00534-w
  10. Bio Protoc. 2019 Jun 05. 9(11): e3255
      Cytosolic rRNAs are highly dynamic and can be degraded under conditions such as apoptosis, starvation and magnesium depletion. The degradation is also related to their specific localization, as fractions of cytosolic ribosomes are localized on the surfaces of intracellular organelles, such as endoplasmic reticulum (ER) and mitochondria. Such localized translation facilitates translocation of nascent proteins into these organelles co-translationally, contributing to fast responses to cellular stresses and precise regulations of the organelle. Here, we describe a protocol to establish the in organello system to investigate rRNA degradation on mitochondrial outer membrane or ER. The protocol consists of organelle isolation, rRNA degradation on organelles and agarose gel electrophoresis to examine the remaining rRNAs.
    Keywords:  Cytosolic rRNAs; ER-associated ribosomes; In organello; Localized translation; Mitochondrion-associated ribosomes; Ribosomal RNA; rRNA degradation
    DOI:  https://doi.org/10.21769/BioProtoc.3255
  11. Bio Protoc. 2019 Jul 20. 9(14): e3307
      The kinase/RNase IRE1 is a key effector of the cellular response to endoplasmic reticulum stress. The RNase activity of IRE1 can be measured in cells or in the test tube. Here we describe a protocol for the in vitro cleavage and analysis of RNA substrates of IRE1. The method consists of the in vitro transcription, purification and re-folding of IRE1 substrate RNAs followed by their cleavage using recombinant cytosolic kinase/RNase domains of IRE1 and the separation of the resulting fragments by denaturing polyacrylamide gel electrophoresis. This protocol allows the study of the cleavage kinetics of IRE1's RNA substrates in vitro.
    Keywords:  ER stress; IRE1; RNA cleavage; Regulated IRE1-dependent decay; Unfolded protein response; XBP1
    DOI:  https://doi.org/10.21769/BioProtoc.3307
  12. Aging Cell. 2021 Mar 04. e13331
      Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase (TERT), contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide CRISPR screen to identify gene deletions that sensitized p53-positive human cells to telomerase inhibition. We uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1 (TAPR1), that exhibited a synthetic-sick relationship with TERT loss. A subsequent genome-wide CRISPR screen in TAPR1-disrupted cells reciprocally identified TERT as a sensitizing gene deletion. Cells lacking TAPR1 or TERT possessed elevated p53 levels and transcriptional signatures consistent with p53 upregulation. The elevated p53 response in TERT- or TAPR1-deficient cells was exacerbated by treatment with the MDM2 inhibitor and p53 stabilizer nutlin-3a and coincided with a further reduction in cell fitness. Importantly, the sensitivity to treatment with nutlin-3a in TERT- or TAPR1-deficient cells was rescued by loss of p53. These data suggest that TAPR1 buffers against the deleterious consequences of telomere erosion or DNA damage by constraining p53. These findings identify C16ORF72/TAPR1 as new regulator at the nexus of telomere integrity and p53 regulation.
    Keywords:  C16ORF72; CRISPR-Cas9; Telomere Attrition and P53 Response 1; genome-wide screen; p53; synthetic-sick-lethal; telomerase inhibitor (BIBR1532); telomere erosion
    DOI:  https://doi.org/10.1111/acel.13331
  13. Nat Rev Mol Cell Biol. 2021 Mar 03.
      Transfer RNA (tRNA) is an adapter molecule that links a specific codon in mRNA with its corresponding amino acid during protein synthesis. tRNAs are enzymatically modified post-transcriptionally. A wide variety of tRNA modifications are found in the tRNA anticodon, which are crucial for precise codon recognition and reading frame maintenance, thereby ensuring accurate and efficient protein synthesis. In addition, tRNA-body regions are also frequently modified and thus stabilized in the cell. Over the past two decades, 16 novel tRNA modifications were discovered in various organisms, and the chemical space of tRNA modification continues to expand. Recent studies have revealed that tRNA modifications can be dynamically altered in response to levels of cellular metabolites and environmental stresses. Importantly, we now understand that deficiencies in tRNA modification can have pathological consequences, which are termed 'RNA modopathies'. Dysregulation of tRNA modification is involved in mitochondrial diseases, neurological disorders and cancer.
    DOI:  https://doi.org/10.1038/s41580-021-00342-0
  14. Life (Basel). 2021 Feb 26. pii: 185. [Epub ahead of print]11(3):
      Apoptosis is a form of programmed death that has also been observed in cells infected by several viruses. It is considered one of the most critical innate immune mechanisms that limits pathogen proliferation and propagation before the initiation of the adaptive immune response. Recent studies investigating the cellular responses to SARS-CoV and SARS-CoV-2 infection have revealed that coronaviruses can alter cellular homeostasis and promote cell death, providing evidence that the modulation of apoptotic pathways is important for viral replication and propagation. Despite the genetic diversity among different coronavirus clades and the infection of different cell types and several hosts, research studies in animal coronaviruses indicate that apoptosis in host cells is induced by common molecular mechanisms and apoptotic pathways. We summarize and critically review current knowledge on the molecular aspects of cell-death regulation during animal coronaviruses infection and the viral-host interactions to this process. Future research is expected to lead to a better understanding of the regulation of cell death during coronavirus infection. Moreover, investigating the role of viral proteins in this process will help us to identify novel antiviral targets related to apoptotic signaling pathways.
    Keywords:  animal coronaviruses; apoptosis; apoptotic pathways
    DOI:  https://doi.org/10.3390/life11030185
  15. Front Mol Biosci. 2020 ;7 599332
      In mammalian cells, cell cycle entry occurs in response to the correct stimuli and is promoted by the transcriptional activity of E2F family members. E2F proteins regulate the transcription of S phase cyclins and genes required for DNA replication, DNA repair, and apoptosis. The activity of E2F1, the archetypal and most heavily studied E2F family member, is tightly controlled by the DNA damage checkpoints to modulate cell cycle progression and initiate programmed cell death, when required. Altered tumor suppressor and oncogenic signaling pathways often result in direct or indirect interference with E2F1 regulation to ensure higher rates of cell proliferation independently of external cues. Despite a clear link between dysregulated E2F1 activity and cancer progression, literature on the contribution of E2F1 to DNA replication stress phenotypes is somewhat scarce. This review discusses how dysfunctional tumor suppressor and oncogenic signaling pathways promote the disruption of E2F1 transcription and hence of its transcriptional targets, and how such events have the potential to drive DNA replication stress. In addition to the involvement of E2F1 upstream of DNA replication stress, this manuscript also considers the role of E2F1 as a downstream effector of the response to this type of cellular stress. Lastly, the review introduces some reflections on how E2F1 activity is integrated with checkpoint control through post-translational regulation, and proposes an exploitable tumor weakness based on this axis.
    Keywords:  DNA replication stress; E2F1; cyclin E; cyclin F; retinoblastoma; ribonucleotide reductase; ubiquitin proteasome system
    DOI:  https://doi.org/10.3389/fmolb.2020.599332
  16. Int J Mol Sci. 2021 Feb 11. pii: 1814. [Epub ahead of print]22(4):
      A reduction in daily caloric or nutrient intake has been observed to promote health benefits in mammals and other vertebrates. Feed Restriction (FR), whereby the overall food intake of the organism is reduced, has been explored as a method to improve metabolic and immune health, as well as to optimize productivity in farming. However, less is known regarding the molecular and physiological consequences of FR. Using the model organism, Danio rerio, we investigated the impact of a short-term (month-long) FR on growth, gut morphology and gene expression. Our data suggest that FR has minimal effects on the average growth rates, but it may affect weight and size heterogeneity in a sex-dependent manner. In the gut, we observed a significant reduction in gut circumference and generally lower mucosal heights, whereas other parameters remained unchanged. Gene Ontology (GO), EuKaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified numerous metabolic, reproductive, and immune response pathways that were affected by FR. These results broaden our understanding of FR and contribute towards growing knowledge of its effects on vertebrate health.
    Keywords:  Danio rerio; calorie restriction; feed restriction; gut
    DOI:  https://doi.org/10.3390/ijms22041814
  17. Biology (Basel). 2021 Feb 19. pii: 163. [Epub ahead of print]10(2):
      Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.
    Keywords:  ALS; Alzheimer; DNA damage response; PARP; Parkinson; cGAS-STING; neurodegeneration; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/biology10020163
  18. Front Immunol. 2021 ;12 628966
      Gliomas are the most common and lethal primary malignant tumor of the brain. Routine treatment including surgical resection, chemotherapy, and radiotherapy produced limited therapeutic effect, while immunotherapy targeting the glioma microenvironment has offered a novel therapeutic option. PDIA5 protein is the member of PDI family, which is highly expressed in glioma and participates in glioma progression. Based on large-scale bioinformatics analysis, we discovered that PDIA5 expression level is upregulated in aggressive gliomas, with high PDIA5 expression predicting poor clinical outcomes. We also observed positive correlation between PDIA5 and immune infiltrating cells, immune related pathways, inflammatory activities, and other immune checkpoint members. Patients with high PDIA5 high-expression benefited from immunotherapies. Additionally, immunohistochemistry revealed that PDIA5 and macrophage biomarker CD68 were upregulated in high-grade gliomas, and patients with low PDIA5 level experienced favorable outcomes among 33 glioma patients. Single cell RNA sequencing exhibited that PDIA5 was in high level presenting in neoplastic cells and macrophages. Cell transfection and co-culture of glioma cells and macrophages revealed that PDIA5 in tumor cells mediated macrophages exhausting. Altogether, our findings indicate that PDIA5 overexpression is associated with immune infiltration in gliomas, and may be a promising therapeutic target for glioma immunotherapy.
    Keywords:  PDIA5; gliomas; immune infiltration; immunotherapy; scRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2021.628966
  19. Front Oncol. 2020 ;10 621294
      Ubiquitination, a crucial post-translation modification, regulates the localization and stability of the substrate proteins including nonhistone proteins. The ubiquitin-proteasome system (UPS) on nonhistone proteins plays a critical role in many cellular processes such as DNA repair, transcription, signal transduction, and apoptosis. Its dysregulation induces various diseases including cancer, and the identification of this process may provide potential therapeutic targets for cancer treatment. In this review, we summarize the regulatory roles of key UPS members on major nonhistone substrates in cancer-related processes, such as cell cycle, cell proliferation, apoptosis, DNA damage repair, inflammation, and T cell dysfunction in cancer. In addition, we also highlight novel therapeutic interventions targeting the UPS members (E1s, E2s, E3s, proteasomes, and deubiquitinating enzymes). Furthermore, we discuss the application of proteolysis-targeting chimeras (PROTACs) technology as a novel anticancer therapeutic strategy in modulating protein target levels with the aid of UPS.
    Keywords:  E3 ligase; cancer; deubiquitinase; nonhistone protein; proteolysis-targeting chimeras; ubiquitination
    DOI:  https://doi.org/10.3389/fonc.2020.621294
  20. Nature. 2021 Mar;591(7848): 39-40
      
    Keywords:  Biochemistry; Biological techniques
    DOI:  https://doi.org/10.1038/d41586-021-00236-3
  21. Bio Protoc. 2019 Aug 05. 9(15): e3318
      Post-translational modifications play important roles in controlling protein function and can lead to altered protein stability. Protein stability can be determined after treatment with the protein synthesis inhibitor Cycloheximide. Cycloheximide is a translational inhibitor that inhibits protein synthesis via cytoplasmic ribosomes. Here we describe how to measure the stability of MYC2 in the context of regulation by FERONIA receptor kinase. First, we describe how to measure MYC2 stability in wild-type and feronia mutant; then we describe similar assays in transgenic plants expressing MYC2-FLAG and MYC2A12-FLAG (12 FERONIA phosphorylation sites are mutated to Alanine and the mutant protein is stabilized). MYC2 can be induced by mechanical touch, which can be a confounding factor in protein level measurement. In this protocol, we take that into consideration and try to achieve more accurate measurement.
    Keywords:  FERONIA; Jasmonic acid signaling; MYC2; Plant immunity; Protein degradation; Protein half-life; Protein phosphorylation; Receptor Kinase; Transcription factor
    DOI:  https://doi.org/10.21769/BioProtoc.3318