bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022‒01‒16
six papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. EMBO Rep. 2022 Jan 10. e51679
      The endoplasmic reticulum (ER) is a subcellular organelle crucial for protein folding and calcium storage. Accumulation of unfolded proteins or calcium depletion causes ER stress. Deficiency of ER stress adaptation leads to apoptosis, which is associated with several human disorders. Here, we reveal that ER transmembrane protein EI24 promotes cell adaptation to ER stress by coordinating the IRE1 branch of the unfolded protein response (UPR) and calcium signaling. Under nonstressed conditions, EI24 binds to the kinase domain of IRE1 to inhibit its activation. Upon ER stress, EI24 disassociates from IRE1 to permit UPR activation, and meanwhile targets IP3R1 to prevent ER calcium depletion, which together promote cell adaptation to ER stress. EI24 knockout causes failure of ER stress adaptation and apoptosis. Thus, EI24 is a novel anti-apoptotic factor implicated in ER stress signaling.
    Keywords:  EI24; ER stress; apoptosis; calcium; unfolded protein response
  2. Acta Pharm Sin B. 2021 Dec;11(12): 3983-3993
      Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.
    Keywords:  ASGR, asialoglycoprotein receptor 1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6α/β; BID, twice a day; CLuc, Cypridina luciferase; Cell signaling; Chaperones; Diabetes; EGFP-VSVG, enhanced green fluorescence protein-vesicular stomatitis virus ts045 G protein; ER stress; ER, endoplasmic reticulum; ERP72, endoplasmic reticulum proteins 72; Endoplasmic reticulum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GLuc, Gaussia luciferase; GRP78, 78-kDa glucose-regulated protein; GRPRP94, glucose-regulated protein 94; GSIS, glucose stimulated insulin secretion; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; IL1β, interleukin 1β; INFγ, interferon gamma; IRE1, inositol requiring enzyme 1α/β; Liver; Metabolic diseases; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nod, non-obese diabetic; OGTT, oral glucose tolerance test; PERK, PKR-like ER kinase; Pancreas; Protein folding; SP1/2, serine protease1/2; Small molecules; T1/2D, type1/2 diabetes; TG, thapsigargin; TNFα, tumor necrosis factor alpha; Tm, tunicamycin; UPR, unfolded protein response; Unfolded protein response; XBP1, X-box-binding protein 1; i.p., intraperitoneal; uHTS, ultra-high throughput screening; β cells
  3. Front Microbiol. 2021 ;12 808593
      Coronavirus is an important pathogen with a wide spectrum of infection and potential threats to humans and animals. Its replication occurs in the cytoplasm and is closely related to the endoplasmic reticulum (ER). Studies reported that coronavirus infection causes ER stress, and cells simultaneously initiate unfolded protein response (UPR) to alleviate the disturbance of ER homeostasis. Activation of the three branches of UPR (PERK, IRE1, and ATF6) modulates various signaling pathways, such as innate immune response, microRNA, autophagy, and apoptosis. Therefore, a comprehensive understanding of the relationship between coronavirus and ER stress is helpful to understand the replication and pathogenesis of coronavirus. This paper summarizes the current knowledge of the complex interplay between coronavirus and UPR branches, focuses on the effect of ER stress on coronavirus replication and coronavirus resistance to host innate immunity, and summarizes possible drug targets to regulate the impact of coronavirus infection.
    Keywords:  coronavirus; drug targets; endoplasmic reticulum stress; host innate immunity; unfolded protein response (UPR)
  4. Sci Rep. 2022 Jan 11. 12(1): 504
      We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis.
  5. Clin Sci (Lond). 2022 Jan 14. 136(1): 163-166
      In this commentary, we discuss new observations stating that spliced X-box-binding protein 1 (Xbp1s)-DNA damage-inducible transcript 3 (Ddit3) promotes monocrotaline (MCT)-induced pulmonary hypertension (Jiang et al., Clinical Science (2021) 135(21), Xbp1s-Ddit3 is involved in the regulation of endoplasmic reticulum stress but is also associated with DNA damage repair machinery. Pathologic DNA damage repair mechanisms have emerged as critical determinants of pulmonary hypertension development. We discuss the potential relationship among Xbp1s-Ddit3, DNA damage, and pulmonary hypertension. Although Xbp1s-Ddit3 contributes to the regulation of cell proliferation and apoptosis and the development of vascular lesions, whether Xbp1s is a friend or foe remains controversial.
    Keywords:  DNA damage; pulmonary hypertension; xbp1s
  6. PLoS One. 2022 ;17(1): e0261789
      Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.