bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020–05–03
seven papers selected by
Susan Logue, University of Manitoba
  1. Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress.
  2. TUDCA Inhibits HSV-1 Replication by Modulating Unfolded Protein Response Pathway.
  3. Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress.
  4. Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.
  5. Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response.
  6. α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells.
  7. Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress.
  1. J Cell Biol. 2020 Jul 06. pii: e201909165. [Epub ahead of print]219(7):
    Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress.
    Nurulain Ho, Wei Sheng Yap, Jiaming Xu, Haoxi Wu, Jhee Hong Koh, Wilson Wen Bin Goh, Bhawana George, Shu Chen Chong, Stefan Taubert, Guillaume Thibault.
      Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.
    DOI:  https://doi.org/10.1083/jcb.201909165
  2. J Med Virol. 2020 May 01.
    TUDCA Inhibits HSV-1 Replication by Modulating Unfolded Protein Response Pathway.
    Airong Su, Huanru Wang, Datong Zheng, Zhiwei Wu.
      Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, was used to protect liver function through anti-apoptosis or reducing endoplasmic reticulum stress (ER stress). Previous studies showed that ER stress was modulated by HSV-1 infection to facilitate viral replication. Here, we investigated the effect of TUDCA on HSV-1 infection of HEC-1-A cells and showed that both replication and multiplication of the virus were inhibited by TUDCA in a dose dependent manner. Unfolded protein response (UPR) was induced in order to deliver stress signals from ER to nucleus. We found that TUDCA alleviated ATF6 branch inhibition, partially enhanced PERK pathway activation and repressed IRE1α arm activation significantly in infected cells. The findings of this study suggest that TUDCA inhibits HSV-1 replication through ER stress pathway, which may provide a potential therapeutic strategy for HSV-1 infection. This article is protected by copyright. All rights reserved.
    Keywords:  Herpes simplex virus types 1 (HSV-1); Tauroursodeoxycholic acid (TUDCA); Unfolded protein response (UPR); activating transcription factor 6 (ATF6); inositol-requiring protein 1α (IRE1α); protein kinase RNA-like ER kinase (PERK)
    DOI:  https://doi.org/10.1002/jmv.25963
  3. Cells. 2020 Apr 26. pii: E1078. [Epub ahead of print]9(5):
    Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress.
    Tae Won Ha, Ji Hun Jeong, HyeonSeok Shin, Hyun Kyu Kim, Jeong Suk Im, Byung Hoo Song, Jacob Hanna, Jae Sang Oh, Dong-Hun Woo, Jaeseok Han, Man Ryul Lee.
      Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts. Compared to fibroblasts, electron microscopy showed simpler/fewer structures with fewer networks in the endoplasmic reticulum (ER) of hPSCs, as well as lower expression of ER-related genes according to meta-analysis. As hPSCs contain low levels of binding immunoglobulin protein (BiP), an ER chaperone, thapsigargin treatment sharply increased the gene expression of the unfolded protein response. Thus, hPSCs with decreased chaperone function reacted sensitively to ER stress and entered apoptosis faster than fibroblasts. Such ER stress-induced apoptotic processes were abolished by tauroursodeoxycholic acid, an ER-stress reliever. Hence, our results revealed that as PSCs have an underdeveloped structure and express fewer BiP chaperone proteins than somatic cells, they are more susceptible to ER stress-induced apoptosis in response to stress.
    Keywords:  C/EBP homologous protein (CHOP); ER stress; binding immunoglobulin protein (BiP); endoplasmic reticulum (ER); human pluripotent stem cells; proteostasis
    DOI:  https://doi.org/10.3390/cells9051078
  4. Cell Death Discov. 2020 ;6 22
    Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.
    Lara Bellini, Thomas Strub, Nadia Habel, Charlotte Pandiani, Sandrine Marchetti, Arnaud Martel, Stéphanie Baillif, Béatrice Bailly-Maitre, Philippe Gual, Robert Ballotti, Corine Bertolotto.
      To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.
    Keywords:  Cell death; Eye cancer
    DOI:  https://doi.org/10.1038/s41420-020-0259-2
  5. J Mol Cell Cardiol. 2020 Apr 24. pii: S0022-2828(20)30094-8. [Epub ahead of print]
    Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response.
    Erik A Blackwood, Donna J Thuerauf, Miroslava Stastna, Haley Stephens, Zoe Sand, Amber Pentoney, Khalid Azizi, Tobias Jakobi, Jennifer E Van Eyk, Hugo A Katus, Christopher C Glembotski, Shirin Doroudgar.
      The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the ER stressor thapsigargin (TG), which depletes ER calcium, induced death of cultured neonatal rat ventricular myocytes (NRVMs) in high media volume but fostered protection in low media volume. In contrast, another ER stressor, tunicamycin (TM), a protein glycosylation inhibitor, induced NRVM death in all media volumes, suggesting that protective proteins were secreted in response to TG but not TM. Proteomic analyses of TG- and TM-conditioned media showed that the secretion of most proteins was inhibited by TG and TM; however, secretion of several ER-resident proteins, including GRP78 was increased by TG but not TM. Simulated ischemia, which decreases SR/ER calcium also increased secretion of these proteins. Mechanistically, secreted GRP78 was shown to enhance survival of NRVMs by collaborating with a cell-surface protein, CRIPTO, to activate protective AKT signaling and to inhibit death-promoting SMAD2 signaling. Thus, proteins secreted during ER stress mediated by ER calcium depletion can enhance cardiac myocyte viability.
    Keywords:  Cardiac myocyte death; Cardiokine; Cardioprotection; ER stress; Heart failure; Proteostasis
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.04.012
  6. Sci Rep. 2020 Apr 28. 10(1): 7139
    α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells.
    Monica Pibiri, Pia Sulas, Tania Camboni, Vera Piera Leoni, Gabriella Simbula.
      Hepatocellular carcinoma (HCC) is the most common liver cancer and a major cause of adult death. The current treatments for HCC suffer from drug resistance and poor prognosis; therefore, novel therapeutic agents are urgently needed. Phytochemicals have been proposed to treat a range of cancers. Among them, α-lipoic acid (α-LA), a naturally synthesized antioxidant found in various dietary animal and plant sources, prevents oxidant-mediated cell death in normal cells while inducing apoptosis in several cancer cell lines. Previously, we demonstrated that the treatment of hepatoma cells with α-LA induced apoptosis, which was preceded by the generation of reactive oxygen species (ROS) and activation of the p53 protein, a known inducer of mitochondria-mediated apoptosis. Several studies have shown that ROS-induced apoptosis is associated with endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) activation. Herein, we investigated if α-LA-induced apoptosis in hepatoma cell lines was ER stress- and UPR-mediated by gene expression profiling analyses. UPR and ER stress pathways were the most up-regulated after treatment with α-LA. This finding, which has been confirmed by expression analyses of ER- and UPR-associated proteins, provides a better understanding of the molecular mechanisms behind the anti-tumoral action of α-LA on hepatoma cells.
    DOI:  https://doi.org/10.1038/s41598-020-64004-5
  7. FASEB J. 2020 Apr 29.
    Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress.
    Tao Shen, Zihang Huang, Chengfei Shi, Xiaofan Pu, Xiaodong Xu, Zhengrong Wu, Guoping Ding, Liping Cao.
      Pancreatic cancer is the fourth most lethal malignancy and is characterized by poor immunogenicity. Pancreatic cancer cells have various strategies to suppress host immune response, evade immune defenses, and facilitate tumor growth and development. As a mode of long-range intercellular communication, cancer-derived exosomes contribute to impairment of the immune system. However, the mechanisms that induce changes in the activities of signal transduction pathways in immune cells, which are influenced by tumor-derived exosomes, are poorly understood. We (1) treated peripheral T lymphocytes with pancreatic cancer-derived exosomes, tagged CD63 with tdTomato, to trace exosome transfer from pancreatic cancer cells to T lymphocytes; (2) carried out a cytotoxicity assay of exosome-treated T lymphocytes using the Real Time Cellular Analysis system; (3) performed RNA sequencing and gene set enrichment analysis to explore the pivotal signaling pathway that mediates apoptosis in exosome-treated T lymphocytes; and (4) demonstrated the role of p38 mitogen-activated protein kinase (MAPK) and endoplasmic reticulum (ER) stress in exosome-induced T-lymphocyte apoptosis. In conclusion, these results indicate that pancreatic cancer cells secrete exosomes, which are taken up by T lymphocytes to activate p38 MAPK, and then induce ER stress-mediated apoptosis, ultimately causing immunosuppression.
    Keywords:  T lymphocytes; apoptosis; endoplasmic reticulum stress; exosomes; p38 MAPK; pancreatic cancer
    DOI:  https://doi.org/10.1096/fj.201902186R
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