bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒02‒28
sixteen papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital


  1. Front Cell Neurosci. 2020 ;14 615125
      Diabetic retinopathy (DR) is a vision-threatening, chronic, and challenging eye disease in the diabetic population. Despite recent advancements in the clinical management of diabetes, DR remains the major cause of blindness in working-age adults. A better understanding of the molecular and cellular basis of DR development will aid in identifying therapeutic targets. Emerging pieces of evidence from recent research in the field of ER stress have demonstrated a close association between unfolded protein response (UPR)-associated cellular activities and DR development. In this minireview article, we shall provide an emerging understating of how UPR influences DR pathogenesis at the cellular level.
    Keywords:  diabetic retinopathy; retinal glial cell; retinal neuronal cell; retinal pigment epithelium; retinal vascular cell; unfolded protein response
    DOI:  https://doi.org/10.3389/fncel.2020.615125
  2. Nat Rev Cardiol. 2021 Feb 22.
      Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.
    DOI:  https://doi.org/10.1038/s41569-021-00511-w
  3. J Biol Chem. 2021 Feb 19. pii: S0021-9258(21)00213-1. [Epub ahead of print] 100440
      Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipid breakdown and release from adipocytes via lipolysis in a separate way from hormones or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis from adrenergic or hormonal stimuli. Our data show that inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. IRE1-mediated lipolysis was specific for inflammatory triggers since IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. Inhibiting IRE1 kinase activity blocked NF-κB activation, interleukin-6 secretion, and adipocyte-autonomous lipolysis from inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, suggesting that inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. We found no role for canonical unfolded protein responses or ABL kinases in linking ER stress to IRE1-mediated lipolysis. Adiponectin-Cre-mediated IRE1 knockout in mice showed that adipocyte IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue explants and that adipocyte IRE1 was required for approximately half of the increase in blood triglycerides after a bacterial endotoxin-mediated inflammatory stimulus in vivo. Together, our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.
    Keywords:  ER stress; adipocyte; cytokine; endocrinology; immunometabolism; inflammation; lipid; lipolysis; metabolic syndrome; obesity
    DOI:  https://doi.org/10.1016/j.jbc.2021.100440
  4. Sci Rep. 2021 Feb 24. 11(1): 4506
      Upon endoplasmic-reticulum (ER) stress, the ER-located transmembrane protein, Ire1, is autophosphorylated and acts as an endoribonuclease to trigger the unfolded protein response (UPR). Previous biochemical studies have shown that Ire1 exhibits strong endoribonuclease activity when its cytosolic kinase region captures ADP. Here, we asked how this event contributes to the regulation of Ire1 activity. At the beginning of this study, we obtained a luminal-domain mutant of Saccharomyces cerevisiae Ire1, deltaIdeltaIIIdeltaV/Y225H Ire1, which is deduced to be controlled by none of the luminal-side regulatory events. ER-stress responsiveness of deltaIdeltaIIIdeltaV/Y225H Ire1 was largely compromised by a further mutation on the kinase region, D797N/K799N, which allows Ire1 to be activated without capturing ADP. Therefore, in addition to the ER-luminal domain of Ire1, which monitors ER conditions, the kinase region is directly involved in the ER-stress responsiveness of Ire1. We propose that potent ER stress harms cells' "vividness", increasing the cytosolic ADP/ATP ratio, and eventually strongly activates Ire1. This mechanism seems to contribute to the suppression of inappropriately potent UPR under weak ER-stress conditions.
    DOI:  https://doi.org/10.1038/s41598-021-83890-x
  5. Trends Cell Biol. 2021 Feb 18. pii: S0962-8924(21)00023-4. [Epub ahead of print]
      Accurate duplication of chromosomal DNA is vital for faithful transmission of the genome during cell division. However, DNA replication integrity is frequently challenged by genotoxic insults that compromise the progression and stability of replication forks, posing a threat to genome stability. It is becoming clear that the organization of the replisome displays remarkable flexibility in responding to and overcoming a wide spectrum of fork-stalling insults, and that these transactions are dynamically orchestrated and regulated by protein post-translational modifications (PTMs) including ubiquitylation. In this review, we highlight and discuss important recent advances on how ubiquitin-mediated signaling at the replication fork plays a crucial multifaceted role in regulating replisome composition and remodeling its configuration upon replication stress, thereby ensuring high-fidelity duplication of the genome.
    Keywords:  DNA damage; DNA repair; DNA replication; genome stability; replication stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2021.01.008
  6. Mol Cell Endocrinol. 2021 Feb 23. pii: S0303-7207(21)00062-9. [Epub ahead of print] 111218
      Maternal obesity malprograms offspring obesity and associated metabolic disorder. As a common phenomenon in obesity, endoplasmic reticulum (ER) stress also presents early prior to the development. Here, we investigate metabolic effect of early activated hypothalamic ER stress in offspring exposed to maternal obesogenic environment and the underlying mechanism in ICR mice model. We found higher body weight, hyperphagia and defective hypothalamic feeding-circuit in the offspring born to obese dams, with hypothalamic ER stress, and even more comprehensive cell proteotoxic stress were induced during the early postnatal period. However, neonatal inhibition of hypothalamic ER stress worsened the metabolic end. We believe that the uncoordinated interaction between the unfolded protein response and the heat shock response, regulated by heat shock protein 70, might be responsible for the malformed hypothalamic feeding circuit of the offspring exposure to maternal obesogenic conditions and were linked with deleterious metabolism in adulthood, especially when exposure to high-energy conditions.
    Keywords:  Feeding circuit development; Heat shock response; Hypothalamic ER stress; Maternal obesity; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.mce.2021.111218
  7. J Cell Mol Med. 2021 Feb 21.
      Endoplasmic reticulum (ER) stress has considerable impact on cell growth, proliferation, metastasis, invasion, angiogenesis and chemoradiotherapy resistance in various cancers. However, the effect of ER stress on the outcomes of glioma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TCGA) glioma data set to reflect immune characteristics and predict the prognosis of glioma patients. Survival analysis indicated that there were significant differences in the overall survival (OS) of glioma patients with different ER stress-related risk scores. Moreover, the ER stress-related risk signature, which was markedly associated with the clinicopathological properties of glioma patients, could serve as an independent prognostic indicator. Functional enrichment analysis revealed that the risk model correlated with immune and inflammation responses, as well as biosynthesis and degradation. In addition, the ER stress-related risk model indicated an immunosuppressive microenvironment. In conclusion, we present an ER stress risk model that is an independent prognostic factor and indicates the general immune characteristics in the glioma microenvironment.
    Keywords:  endoplasmic reticulum stress; endoplasmic reticulum stress risk model; glioma; immunosuppressive; overall survival; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.16321
  8. Cell Mol Life Sci. 2021 Feb 25.
      Innate immunity is an evolutionary ancient defence strategy that serves to eliminate infectious agents while maintaining host health. It involves a complex network of sensors, signaling proteins and immune effectors that detect the danger, then relay and execute the immune programme. Post-translational modifications relying on conserved ubiquitin and ubiquitin-like proteins are an integral part of the system. Studies using invertebrate models of infection, such as the nematode Caenorhabditis elegans, have greatly contributed to our understanding of how ubiquitin-related processes act in immune sensing, regulate immune signaling pathways, and participate to host defence responses. This review highlights the interest of working with a genetically tractable model organism and illustrates how C. elegans has been used to identify ubiquitin-dependent immune mechanisms, discover novel ubiquitin-based resistance strategies that mediate pathogen clearance, and unravel the role of ubiquitin-related processes in tolerance, preserving host fitness during pathogen attack. Special emphasis is placed on processes that are conserved in mammals.
    Keywords:  Host–pathogen interaction; Proteostasis; SUMOylation; Ubiquitination; Unfolded protein response
    DOI:  https://doi.org/10.1007/s00018-021-03787-w
  9. Front Cell Dev Biol. 2021 ;9 627700
      The endoplasmic reticulum (ER) forms direct membrane contact sites with the plasma membrane (PM) in eukaryotic cells. These ER-PM contact sites play essential roles in lipid homeostasis, ion dynamics, and cell signaling, which are carried out by protein-protein or protein-lipid interactions. Distinct tethering factors dynamically control the architecture of ER-PM junctions in response to intracellular signals or external stimuli. The physiological roles of ER-PM contact sites are dependent on a variety of regulators that individually or cooperatively perform functions in diverse cellular processes. This review focuses on proteins functioning at ER-PM contact sites and highlights the recent progress in their mechanisms and physiological roles.
    Keywords:  endoplasmic reticulum (ER); enzyme; lipid transfer; membrane contact sites (MCSs); plasma membrane; tether
    DOI:  https://doi.org/10.3389/fcell.2021.627700
  10. J Cell Sci. 2021 Feb 23. pii: jcs.249276. [Epub ahead of print]
      A genome-wide screen recently identified SEC24A as a novel mediator of thapsigargin-induced cell death in HAP1 cells. Here, we determined the cellular mechanism and specificity of SEC24A-mediated cytotoxicity. Measurement of calcium levels using organelle-specific fluorescent indicator dyes showed that calcium efflux from endoplasmic reticulum (ER) and influx into mitochondria were significantly impaired in SEC24A knockout cells. Furthermore, SEC24A knockout cells also showed ∼44% less colocalization of mitochondria and peripheral tubular ER. Knockout of SEC24A, but not its paralogs SEC24B, SEC24C, or SEC24D, rescued HAP1 cells from cell death induced by three different inhibitors of Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase (SERCA) but not from cell death induced by a topoisomerase inhibitor. Thapsigargin-treated SEC24A knockout cells showed a ∼2.5-fold increase in autophagic flux and ∼10-fold reduction in apoptosis compared to wild-type cells. Taken together, our findings indicate that SEC24A plays a previously unrecognized role in regulating association and calcium flux between the ER and mitochondria, thereby impacting processes dependent on mitochondrial calcium levels, including autophagy and apoptosis.
    Keywords:  Apoptosis; Autophagy; Calcium; ER stress; Mitochondrial-associated membranes; SEC24A; SERCA; Thapsigargin
    DOI:  https://doi.org/10.1242/jcs.249276
  11. Nature. 2021 Feb 24.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-021-00429-w
  12. Front Pharmacol. 2020 ;11 629266
      DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.
    Keywords:  DNA damage; DNA repair pathways; cancer therapy; drug resistance; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fphar.2020.629266
  13. Mol Cell. 2021 Jan 28. pii: S1097-2765(21)00055-1. [Epub ahead of print]
      Remdesivir is a nucleoside analog approved by the US FDA for treatment of COVID-19. Here, we present a 3.9-Å-resolution cryo-EM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase complex, revealing full incorporation of 3 copies of remdesivir monophosphate (RMP) and a partially incorporated fourth RMP in the active site. The structure reveals that RMP blocks RNA translocation after incorporation of 3 bases following RMP, resulting in delayed chain termination, which can guide the rational design of improved antiviral drugs.
    Keywords:  COVID-19 treatment; RNA-dependent RNA polymerase; SARS-CoV-2; remdesivir
    DOI:  https://doi.org/10.1016/j.molcel.2021.01.035
  14. J Cancer Immunol (Wilmington). 2020 ;2(3): 103-115
      Endoplasmic reticulum oxidoreductin-1 alpha (ERO1α) was originally shown to be an endoplasmic reticulum (ER) resident protein undergoing oxidative cycles in concert with protein disulfide isomerase (PDI) to promote proper protein folding and to maintain homeostasis within the ER. ERO1α belongs to the flavoprotein family containing a flavin adenine dinucleotide utilized in transferring of electrons during oxidation-reduction cycles. This family is used to maintain redox potentials and protein homeostasis within the ER. ERO1α's location and function has since been shown to exist beyond the ER. Originally thought to exist solely in the ER, it has since been found to exist in the golgi apparatus, as well as in exosomes purified from patient samples. Besides aiding in protein folding of transmembrane and secretory proteins in conjunction with PDI, ERO1α is also known for formation of de novo disulfide bridges. Public databases, such as the Cancer Genome Atlas (TCGA) and The Protein Atlas, reveal ERO1α as a poor prognostic marker in multiple disease settings. Recent evidence indicates that ERO1α expression in tumor cells is a critical determinant of metastasis. However, the impact of increased ERO1α expression in tumor cells extends into the tumor microenvironment. Secretory proteins requiring ERO1α expression for proper folding have been implicated as being involved in immune escape through promotion of upregulation of programmed death ligand-1 (PD-L1) and stimulation of polymorphonuclear myeloid derived suppressor cells (PMN-MDSC's) via secretion of granulocytic colony stimulating factor (G-CSF). Hereby, ERO1α plays a pivotal role in cancer progression and potentially immune escape; making ERO1α an emerging attractive putative target for the treatment of cancer.
    Keywords:  Cancer; Cancer therapeutics; ER stress; ERO1; Immune resistance
    DOI:  https://doi.org/10.33696/cancerimmunol.2.023
  15. PLoS Biol. 2021 Feb 25. 19(2): e3001122
      The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.
    DOI:  https://doi.org/10.1371/journal.pbio.3001122
  16. Cell Death Dis. 2021 Feb 24. 12(2): 204
      Apoptosis related protein in TGF-β signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-β, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.
    DOI:  https://doi.org/10.1038/s41419-021-03463-8