bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020–01–19
six papers selected by
Susan Logue, University of Manitoba
  1. Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α.
  2. X-box binding protein 1 (XBP1): A key protein for renal osmotic adaptation. Its role in lipogenic program regulation.
  3. FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.
  4. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.
  5. TNFα Selectively Activates the IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in Human Airway Smooth Muscle Cells.
  6. lncRNA H19 sponging miR-93 to regulate inflammation in retinal epithelial cells under hyperglycemia via XBP1s.
  1. Biomed Res Int. 2019 ;2019 3480569
    Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α.
    Zarith Nameyrra Md Nesran, Nurul Husna Shafie, Amirah Haziyah Ishak, Norhaizan Mohd Esa, Amin Ismail, Siti Farah Md Tohid.
      Epigallocatechin-3-gallate (EGCG) is the most abundant bioactive polyphenolic compound among the green tea constituents and has been identified as a potential anticancer agent in colorectal cancer (CRC) studies. This study was aimed to determine the mechanism of actions of EGCG when targeting the endoplasmic reticulum (ER) stress pathway in CRC. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed on HT-29 cell line and normal cell line (3T3) to determine the EGCG toxicity. Next, western blot was done to observe the expression of the related proteins for the ER stress pathway. The Caspase 3/7 assay was performed to determine the apoptosis induced by EGCG. The results demonstrated that EGCG treatment was toxic to the HT-29 cell line. EGCG induced ER stress in HT-29 by upregulating immunoglobulin-binding (BiP), PKR-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α), activating transcription 4 (ATF4), and inositol-requiring kinase 1 alpha (IRE1α). Apoptosis was induced in HT-29 cells after the EGCG treatment, as shown by the Caspase 3/7 activity. This study indicates that green tea EGCG has the potential to inhibit colorectal cancer cells through the induction of ER stress.
    DOI:  https://doi.org/10.1155/2019/3480569
  2. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jan 09. pii: S1388-1981(20)30008-1. [Epub ahead of print] 158616
    X-box binding protein 1 (XBP1): A key protein for renal osmotic adaptation. Its role in lipogenic program regulation.
    Cecilia Casali, Ricardo Malvicini, Luciana Erjavec, Leandro Parra, Ayelen Artuch, María C Fernández Tome.
      In renal cells, hyperosmolarity can induce cellular stress or differentiation. Both processes require active endoplasmic reticulum (ER)-associated protein synthesis. Lipid biosynthesis also occurs at ER surface. We showed that hyperosmolarity upregulates glycerophospholipid (GP) and triacylglycerol (GL-TG) de novo synthesis. Considering that massive synthesis of proteins and/or lipids may drive to ER stress, herein we evaluated whether hyperosmolar environment induces ER stress and the participation of inositol-requiring enzyme 1α (IRE1α)-XBP1 in hyperosmotic-induced lipid synthesis. Treatment of Madin-Darby canine kidney (MDCK) cells with hyperosmolar medium triggered ER stress-associated unfolded protein response (UPR). Hyperosmolarity significantly increased xbp1 mRNA and protein as function of time; 24 h of treatment raised the spliced form of XBP1 protein (XBP1s) and induced its translocation to nuclear compartment where it can act as a transcription factor. XBP1 silencing or IRE1α ribonuclease (RNAse) inhibition impeded the expression of lipin1, lipin2 and diacylglycerol acyl transferase-1 (DGAT1) enzymes which yielded decreased GL-TG synthesis. The lack of XBP1s also decreased sterol regulatory element binding protein (SREBP) 1 and 2. Together our data demonstrate that hyperosmolarity induces IRE1α → XBP1s activation; XBP1s drives the expression of SREBP1 and SREBP2 which in turn regulates the expression of the lipogenic enzymes lipin1 (LPIN1) and 2 (LPIN2) and DGAT1. We also demonstrated for the first time that tonicity-responsive enhancer binding protein (TonEBP), the master regulator of osmoprotective response, regulates XBP1 expression. Thus, XBP1 acts as an osmoprotective protein since it is activated by high osmolarity and upregulates lipid metabolism, membranes generation and the restoration of ER homeostasis.
    Keywords:  ER stress; Hyperosmolarity; Lipogenic enzymes; SREBP; XBP1
    DOI:  https://doi.org/10.1016/j.bbalip.2020.158616
  3. EMBO J. 2020 Jan 13. e102608
    FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.
    Xiao Jiang, Xinyi Wang, Xianming Ding, Mengjie Du, Boran Li, Xialian Weng, Jingzi Zhang, Lin Li, Rui Tian, Qi Zhu, She Chen, Liang Wang, Wei Liu, Lei Fang, Dante Neculai, Qiming Sun.
      Degradation of endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.
    Keywords:  CAMK2B; ER stress; ER-phagy; FAM134B oligomerization; membrane fragmentation
    DOI:  https://doi.org/10.15252/embj.2019102608
  4. Nat Commun. 2020 Jan 17. 11(1): 348
    TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.
    Yanfeng Liu, Shishi Tao, Lijuan Liao, Yang Li, Hongchang Li, Zhihuan Li, Lilong Lin, Xiaochun Wan, Xiaolu Yang, Liang Chen.
      Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.
    DOI:  https://doi.org/10.1038/s41467-019-14190-2
  5. Am J Physiol Lung Cell Mol Physiol. 2020 Jan 15.
    TNFα Selectively Activates the IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in Human Airway Smooth Muscle Cells.
    John Yap, Xujiao Chen, Philippe F Delmotte, Gary C Sieck.
      Airway inflammation is a key aspect of diseases such as asthma. Pro-inflammatory cytokines such as TNFα mediate the inflammatory response. In various diseases,inflammation leads to endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins, which triggers homeostatic responses to restore normal cellular function. We hypothesized that TNFα triggers ER stress through an increase in ROS generation in human airway smooth muscle (hASM) with downstream effect on mitofusin 2 (Mfn2). In hASM cells isolated from lung specimens incidental to patient surgery, dose and time dependent effects of TNFα exposure were assessed. Exposure of hASM to tunicamycin was used as a positive control. Tempol (500 μM) was used as superoxide scavenger. Activation of three ER stress pathways were evaluated by Western blot: 1) autophosphorylation of IRE1α leading to splicing of XBP1; 2) autophosphorylation PERK leading to phosphorylation of eIF2α; and 3) translocation and cleavage of ATF6. We found that exposure of hASM cells to tunicamycin activated all three ER stress pathways. In contrast, TNFα selectively activated the IRE1α/XBP1 pathway in a dose and time dependent fashion. Our results indicate that TNFα does not activate the PERK and ATF6 pathways. Exposure of hASM cells to TNFα also decreased Mfn2 protein expression. Concurrent exposure to TNFα and Tempol reversed the effect of TNFα on IRE1α phosphorylation and Mfn2 protein expression. Selective activation of the IRE1α/XBP1 pathway in hASM cells after exposure to TNFα may reflect a unique homeostatic role of this pathway in the inflammatory response of hASM cells.
    Keywords:  ER Stress; Inflammation; airway smooth muscle; asthma; cytokine
    DOI:  https://doi.org/10.1152/ajplung.00212.2019
  6. Inflamm Res. 2020 Jan 17.
    lncRNA H19 sponging miR-93 to regulate inflammation in retinal epithelial cells under hyperglycemia via XBP1s.
    Rong Luo, Fan Xiao, Pei Wang, Yu-Xiang Hu.
       OBJECTIVE: Diabetic retinopathy (DR) is a major complication of both type 1 and type 2 diabetes. Recently, inflammation was found to play an important role in DR pathogenesis. But the mechanism has not been fully understood.
    METHODS: ARPE-19 cells were cultured under normal condition and high-glucose condition, then the expressions of miR-93, XBP1s and lncRNA H19 were measured using RT-qPCR or western blots. Besides, the mRNA level of eIF2α and GRP78 and protein level of p-eIF2α and GRP78 were measured by RT-qPCR or western blots. In addition, RT-qPCR and ELISA were adopted to examine the expression and secretion of cytokine factors in these conditions. Dual-luciferase reporter gene assay was used to elucidate the binding and regulation among XBP1s, miR-93 and H19. RNA immunoprecipitation was also performed to verify the interaction between H19 and miR-93. The expressions of DNAJC3 and DNAJB9, the downstream targets of XBP1s, were detected by RT-qPCR.
    RESULTS: We identified that H19 and XBP1s were down-regulated in ARPE-19 cells under high-glucose condition, while miR-93 was up-regulated. ER stress inducers TM and IRE1 inhibitor STF-083010 were adopted and data suggest that ER stress could be induced during high-glucose treatment. In addition, the altered expressions of miR-93, XBP1s and H19 might mediate the increased level of pro-inflammatory cytokines. Furthermore, miR-93 interacted with either lncRNA H19 or XBP1s then modulating the inflammatory processes.
    CONCLUSIONS: H19 played an important role in regulating inflammatory processes in retinal endothelial cells under high-glucose condition through modulating miR-93/XBP1s axis.
    Keywords:  Diabetic retinopathy; H19; Inflammation; Long non-coding RNA; MicroRNA; miR-93
    DOI:  https://doi.org/10.1007/s00011-019-01312-1
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