bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒06‒21
eight papers selected by
Susan Logue
University of Manitoba
  1. Endoplasmic Reticulum (ER) Stress Response Failure in Diseases.
  2. The role of sphingolipids in endoplasmic reticulum stress.
  3. Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities.
  4. FOXO1 promotes HIV latency by suppressing ER stress in T cells.
  5. Activated α2-macroglobulin binding to cell surface GRP78 induces trophoblastic cell fusion.
  6. UBR E3 ligases and the PDIA3 protease control degradation of unfolded antibody heavy chain by ERAD.
  7. miR-410-3p is induced by vemurafenib via ER stress and contributes to resistance to BRAF inhibitor in melanoma.
  8. Differential activation of eMI by distinct forms of cellular stress.
  1. Trends Cell Biol. 2020 Jun 16. pii: S0962-8924(20)30101-X. [Epub ahead of print]
    Endoplasmic Reticulum (ER) Stress Response Failure in Diseases.
    Kashi Raj Bhattarai, Manoj Chaudhary, Hyung-Ryong Kim, Han-Jung Chae.
      Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.
    Keywords:  ER proteostasis; ER stress; ER stress response failure; aging; metabolic diseases; sXBP1
    DOI:  https://doi.org/10.1016/j.tcb.2020.05.004
  2. FEBS Lett. 2020 Jun 15.
    The role of sphingolipids in endoplasmic reticulum stress.
    Woo-Jae Park, Joo-Won Park.
      The endoplasmic reticulum (ER) is an important intracellular compartment in eukaryotic cells and has diverse functions, including protein synthesis, protein folding, lipid metabolism, and calcium homeostasis. ER functions are disrupted by various intracellular and extracellular stimuli that cause ER stress, including the inhibition of glycosylation, disulphide bond reduction, ER calcium store depletion, impaired protein transport to the Golgi, excessive ER protein synthesis, impairment of ER-associated-protein-degradation, and mutated ER protein expression. Distinct ER stress signalling pathways, which are known as the unfolded protein response, are deployed to maintain ER homeostasis, and a failure to reverse ER stress triggers cell death. Sphingolipids are lipids that are structurally characterized by long-chain bases, including sphingosine or dihydrosphingosine (also known as sphinganine). Sphingolipids are bioactive molecules long known to regulate various cellular processes, including cell proliferation, migration, apoptosis, and cell-cell interaction. Recent studies have uncovered that specific sphingolipids are involved in ER stress. This review summarizes the roles of sphingolipids in ER stress and human diseases in the context of pathogenic events.
    Keywords:  Sphingolipid; acyl chain length; ceramide; disease; endoplasmic reticulum stress
    DOI:  https://doi.org/10.1002/1873-3468.13863
  3. Trends Cancer. 2020 Jun 12. pii: S2405-8033(20)30167-9. [Epub ahead of print]
    Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities.
    Ali Khateb, Ze'ev A Ronai.
      Understanding genetic and epigenetic changes that underlie abnormal proliferation of hematopoietic stem and progenitor cells is critical for development of new approaches to monitor and treat leukemia. The unfolded protein response (UPR) is a conserved adaptive signaling pathway that governs protein folding, secretion, and energy production and serves to maintain protein homeostasis in various cellular compartments. Deregulated UPR signaling, which often occurs in hematopoietic stem cells and leukemia, defines the degree of cellular toxicity and perturbs protein homeostasis, and at the same time, offers a novel therapeutic target. Here, we review current knowledge related to altered UPR signaling in leukemia and highlight possible strategies for exploiting the UPR as treatment for this disease.
    Keywords:  endoplasmic reticulum stress; hematological malignancy; hematopoietic stem cell; lymphoid leukemia; myeloid leukemia; unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2020.05.012
  4. Nat Microbiol. 2020 Jun 15.
    FOXO1 promotes HIV latency by suppressing ER stress in T cells.
    Albert Vallejo-Gracia, Irene P Chen, Rosalba Perrone, Emilie Besnard, Daniela Boehm, Emilie Battivelli, Tugsan Tezil, Karsten Krey, Kyle A Raymond, Philip A Hull, Marius Walter, Ireneusz Habrylo, Andrew Cruz, Steven Deeks, Satish Pillai, Eric Verdin, Melanie Ott.
      Quiescence is a hallmark of CD4+ T cells latently infected with human immunodeficiency virus 1 (HIV-1). While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. As a key regulator of T-cell quiescence, FOXO1 promotes latency and suppresses productive HIV infection. We report that, in resting T cells, FOXO1 inhibition impaired autophagy and induced endoplasmic reticulum (ER) stress, thereby activating two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of protein kinase R-like ER kinase, an ER stress sensor that can mediate the induction of ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppressed HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.
    DOI:  https://doi.org/10.1038/s41564-020-0742-9
  5. Sci Rep. 2020 Jun 15. 10(1): 9666
    Activated α2-macroglobulin binding to cell surface GRP78 induces trophoblastic cell fusion.
    Daniel Bastida-Ruiz, Christine Wuillemin, Aude Pederencino, Michal Yaron, Begoña Martinez de Tejada, Salvatore Vincent Pizzo, Marie Cohen.
      The villous cytotrophoblastic cells have the ability to fuse and differentiate, forming the syncytiotrophoblast (STB). The syncytialisation process is essential for placentation. Nevertheless, the mechanisms involved in cell fusion and differentiation are yet to be fully elucidated. It has been suggested that cell surface glucose-regulated protein 78 (GRP78) was involved in this process. In multiple cancer cells, cell membrane-located GRP78 has been reported to act as a receptor binding to the active form of α2-macroglobulin (α2M*), activating thus several cellular signalling pathways implicated in cell growth and survival. We hypothesised that GRP78 interaction with α2M* may also activate signalling pathways in trophoblastic cells, which, in turn, may promote cell fusion. Here, we observed that α2M mRNA is highly expressed in trophoblastic cells, whereas it is not expressed in the choriocarcinoma cell line BeWo. We thus took advantage of forskolin-induced syncytialisation of BeWo cells to study the effect of exogenous α2M* on syncytialisation. We first demonstrated that α2M* induced trophoblastic cell fusion. This effect is dependent on α2M*-GRP78 interaction, ERK1/2 and CREB phosphorylation, and unfolded protein response (UPR) activation. Overall, these data provide novel insights into the signalling molecules and mechanisms regulating trophoblastic cell fusion.
    DOI:  https://doi.org/10.1038/s41598-020-66554-0
  6. J Cell Biol. 2020 Jul 06. pii: e201908087. [Epub ahead of print]219(7):
    UBR E3 ligases and the PDIA3 protease control degradation of unfolded antibody heavy chain by ERAD.
    Danming Tang, Wendy Sandoval, Cynthia Lam, Benjamin Haley, Peter Liu, Di Xue, Deepankar Roy, Tom Patapoff, Salina Louie, Brad Snedecor, Shahram Misaghi.
      Accumulation of unfolded antibody chains in the ER triggers ER stress that may lead to reduced productivity in therapeutic antibody manufacturing processes. We identified UBR4 and UBR5 as ubiquitin E3 ligases involved in HC ER-associated degradation. Knockdown of UBR4 and UBR5 resulted in intracellular accumulation, enhanced secretion, and reduced ubiquitination of HC. In concert with these E3 ligases, PDIA3 was shown to cleave ubiquitinated HC molecules to accelerate HC dislocation. Interestingly, UBR5, and to a lesser degree UBR4, were down-regulated as cellular demand for antibody expression increased in CHO cells during the production phase, or in plasma B cells. Reducing UBR4/UBR5 expression before the production phase increased antibody productivity in CHO cells, possibly by redirecting antibody molecules from degradation to secretion. Altogether we have characterized a novel proteolysis/proteasome-dependent pathway involved in degradation of unfolded antibody HC. Proteins characterized in this pathway may be novel targets for CHO cell engineering.
    DOI:  https://doi.org/10.1083/jcb.201908087
  7. PLoS One. 2020 ;15(6): e0234707
    miR-410-3p is induced by vemurafenib via ER stress and contributes to resistance to BRAF inhibitor in melanoma.
    Tomasz M Grzywa, Klaudia Klicka, Wiktor Paskal, Julia Dudkiewicz, Jarosław Wejman, Michał Pyzlak, Paweł K Włodarski.
      Despite significant development of melanoma therapies, death rates remain high. MicroRNAs, controlling posttranscriptionally gene expression, play role in development of resistance to BRAF inhibitors. The aim of the study was to assess the role of miR-410-3p in response to vemurafenib-BRAF inhibitor. FFPE tissue samples of 12 primary nodular melanomas were analyzed. With the use of Laser Capture Microdissection, parts of tumor, transient tissue, and adjacent healthy tissue were separated. In vitro experiments were conducted on human melanoma cell lines A375, G361, and SK-MEL1. IC50s of vemurafenib were determined using MTT method. Cells were transfected with miR-410-3p mimic, anti-miR-410-3p and their non-targeting controls. ER stress was induced by thapsigargin. Expression of isolated RNA was determined using qRT-PCR. We have found miR-410-3p is downregulated in melanoma tissues. Its expression is induced by vemurafenib in melanoma cells. Upregulation of miR-410-3p level increased melanoma cells resistance to vemurafenib, while its inhibition led to the decrease of resistance. Induction of ER stress increased the level of miR-410-3p. miR-410-3p upregulated the expression of AXL in vitro and correlated with markers of invasive phenotype in starBase. The study shows a novel mechanism of melanoma resistance. miR-410-3p is induced by vemurafenib in melanoma cells via ER stress. It drives switching to the invasive phenotype that leads to the response and resistance to BRAF inhibition.
    DOI:  https://doi.org/10.1371/journal.pone.0234707
  8. Autophagy. 2020 Jun 19.
    Differential activation of eMI by distinct forms of cellular stress.
    Ana Mesquita, James Glenn, Andreas Jenny.
      As one of the major, highly conserved catabolic pathways, autophagy delivers cytosolic components to lysosomes for degradation. It is essential for development, cellular homeostasis, and coping with stress. Reduced autophagy increases susceptibility to protein aggregation diseases and leads to phenotypes associated with aging. Of the three major forms of autophagy, macroautophagy (MA) can degrade organelles or aggregated proteins, and chaperone-mediated autophagy is specific for soluble proteins containing KFERQ-related targeting motifs. During endosomal microautophagy (eMI), cytoplasmic proteins are engulfed into late endosomes in an ESCRT machinery-dependent manner. eMI can be KFERQ-specific or occur in bulk and be induced by prolonged starvation. Its physiological regulation and function, however, are not understood. Here, we show that eMI in the Drosophila fat body, akin to the mammalian liver, is induced upon oxidative or genotoxic stress in an ESCRT and partially Hsc70-4-dependent manner. Interestingly, eMI activation is selective, as ER stress fails to elicit a response. Intriguingly, we find that reducing MA leads to a compensatory enhancement of eMI, suggesting a tight interplay between these degradative processes. Furthermore, we show that mutations in DNA damage response genes are sufficient to trigger eMI and that the response to oxidative stress is under the control of MAPK/JNK signaling. Our data suggest that, controlled by various signaling pathways, eMI allows an organ to react and adapt to specific types of stress and is thus likely critical to prevent disease.
    Keywords:  DNA damage; ER stress; ROS; autophagy; microautophagy; oxidative stress; proteostasis
    DOI:  https://doi.org/10.1080/15548627.2020.1783833
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