bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019–02–10
seven papers selected by
Susan Logue, Apoptosis Research Centre
  1. Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma.
  2. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis.
  3. Unconventional secretion factor GRASP55 is increased by pharmacological unfolded protein response inducers in neurons.
  4. Unfolded protein response is an early, non-critical event during hepatic stellate cell activation.
  5. Tumor Microenvironment Regulation by the ER Stress Transmission Mediator GP73.
  6. IRE1α is critical for kaempferol induced neuroblastoma differentiation.
  7. ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).
  1. Blood. 2019 Feb 08. pii: blood-2018-06-859686. [Epub ahead of print]
    Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma.
    Junling Zhuang, Fazal Shirazi, Ram Kumar Singh, Isere Kuiatse, Hua Wang, Hans C Lee, Zuzana Berkova, Allison Berger, Marc Hyer, Nibedita Chattopadhyay, Sakeena Syed, Judy Qiuju Shi, Jie Yu, Vaishali Shinde, Stephen Tirrell, Richard Julian Jones, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski.
      Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings but drug resistance is an emerging challenge, and this has prompted interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin activating enzyme (UAE), and we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates. This was accompanied by stabilization of many short-lived proteins, including p53, MCL-1, and c-MYC, and activation of the ATF6, IRE-1, and PERK arms of the endoplasmic reticulum stress response pathway, as well as oxidative stress. UAE inhibition showed comparable activity against otherwise isogenic cell lines with wild-type or deleted p53 despite induction of TP53 signaling in wild-type cells. Notably, TAK-243 overcame resistance to conventional drugs and novel agents in cell line models, including bortezomib and carfilzomib resistance, and showed activity against primary cells from relapsed/refractory myeloma patients. In addition, TAK-243 showed strong synergy with a number of anti-myeloma agents, including doxorubicin, melphalan, and panobinostat as measured by low combination indices. Finally, TAK-243 was active against a number of in vivo myeloma models in association with activation of endoplasmic reticulum stress. Taken together, the data support the conclusion that UAE inhibition could be an attractive strategy to move forward to the clinic for patients with relapsed and/or refractory multiple myeloma.
    DOI:  https://doi.org/10.1182/blood-2018-06-859686
  2. Sci Transl Med. 2019 Feb 06. pii: eaau5266. [Epub ahead of print]11(478):
    Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis.
    Dorian A Rosen, Scott M Seki, Anthony Fernández-Castañeda, Rebecca M Beiter, Jacob D Eccles, Judith A Woodfolk, Alban Gaultier.
      Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.
    DOI:  https://doi.org/10.1126/scitranslmed.aau5266
  3. Sci Rep. 2019 Feb 07. 9(1): 1567
    Unconventional secretion factor GRASP55 is increased by pharmacological unfolded protein response inducers in neurons.
    Anna Maria van Ziel, Pablo Largo-Barrientos, Kimberly Wolzak, Matthijs Verhage, Wiep Scheper.
      Accumulation of misfolded proteins in the endoplasmic reticulum (ER), defined as ER stress, results in activation of the unfolded protein response (UPR). UPR activation is commonly observed in neurodegenerative diseases. ER stress can trigger unconventional secretion mediated by Golgi reassembly and stacking proteins (GRASP) relocalization in cell lines. Here we study the regulation of GRASP55 by the UPR upon pharmacological induction of ER stress in primary mouse neurons. We demonstrate that UPR activation induces mRNA and protein expression of GRASP55, but not GRASP65, in cortical neurons. UPR activation does not result in relocalization of GRASP55. UPR-induced GRASP55 expression is reduced by inhibition of the PERK pathway of the UPR and abolished by inhibition of the endonuclease activity of the UPR transducer IRE1. Expression of the IRE1 target XBP1s in the absence of ER stress is not sufficient to increase GRASP55 expression. Knockdown of GRASP55 affects neither induction nor recovery of the UPR. We conclude that the UPR regulates the unconventional secretion factor GRASP55 via a mechanism that requires the IRE1 and the PERK pathway of the UPR in neurons.
    DOI:  https://doi.org/10.1038/s41598-018-38146-6
  4. Cell Death Dis. 2019 Feb 04. 10(2): 98
    Unfolded protein response is an early, non-critical event during hepatic stellate cell activation.
    Inge Mannaerts, Lien F R Thoen, Nathalie Eysackers, Francisco Javier Cubero, Sofia Batista Leite, Iain Coldham, Isabelle Colle, Christian Trautwein, Leo A van Grunsven.
      Hepatic stellate cells activate upon liver injury and help at restoring damaged tissue by producing extracellular matrix proteins. A drastic increase in matrix proteins results in liver fibrosis and we hypothesize that this sudden increase leads to accumulation of proteins in the endoplasmic reticulum and its compensatory mechanism, the unfolded protein response. We indeed observe a very early, but transient induction of unfolded protein response genes during activation of primary mouse hepatic stellate cells in vitro and in vivo, prior to induction of classical stellate cell activation genes. This unfolded protein response does not seem sufficient to drive stellate cell activation on its own, as chemical induction of endoplasmic reticulum stress with tunicamycin in 3D cultured, quiescent stellate cells is not able to induce stellate cell activation. Inhibition of Jnk is important for the transduction of the unfolded protein response. Stellate cells isolated from Jnk knockout mice do not activate as much as their wild-type counterparts and do not have an induced expression of unfolded protein response genes. A timely termination of the unfolded protein response is essential to prevent endoplasmic reticulum stress-related apoptosis. A pathway known to be involved in this termination is the non-sense-mediated decay pathway. Non-sense-mediated decay inhibitors influence the unfolded protein response at early time points during stellate cell activation. Our data suggest that UPR in HSCs is differentially regulated between acute and chronic stages of the activation process. In conclusion, our data demonstrates that the unfolded protein response is a JNK1-dependent early event during hepatic stellate cell activation, which is counteracted by non-sense-mediated decay and is not sufficient to drive the stellate cell activation process. Therapeutic strategies based on UPR or NMD modulation might interfere with fibrosis, but will remain challenging because of the feedback mechanisms between the stress pathways.
    DOI:  https://doi.org/10.1038/s41419-019-1327-5
  5. Hepatology. 2019 Feb 05.
    Tumor Microenvironment Regulation by the ER Stress Transmission Mediator GP73.
    Congwen Wei, Xiaoli Yang, Ning Liu, Jin Geng, Yanhong Tai, Zhenyu Sun, Gangwu Mei, Pengyu Zhou, Yumeng Peng, Chenbin Wang, Xiaoli Zhang, Pingping Zhang, Yunqi Geng, Yujie Wang, Xiaotong Zhang, Xin Liu, Yanhong Zhang, Feixiang Wu, Xiang He, Hui Zhong.
      The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor-promoting inflammation by upregulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of GP73, a Golgi-associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Via GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor-associated macrophages (TAMs) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with GRP78 expression and TAMs density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth and prolonged survival in two mouse HCC models. Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/hep.30549
  6. FEBS J. 2019 Feb 04.
    IRE1α is critical for kaempferol induced neuroblastoma differentiation.
    Ahmad Abdullah, Priti Talwar, Christian Lefebvre d'Hellencourt, Palaniyandi Ravanan.
      Neuroblastoma is an embryonic malignancy that arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecules such as retinoic acid is one of the therapeutic strategies to treat the residual disease. In this study, we have reported the effect of kaempferol in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with kaempferol reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron-specific markers such as β-III tubulin, neuron-specific enolase and NRDG1 (N-myc down-regulated gene 1) revealed the process of differentiation accompanying kaempferol-induced apoptosis. Further analysis to understand the molecular mechanism of action showed that the effect of kaempferol is mediated by the activation of the endoribonuclease activity of IRE1α (Inositol-requiring enzyme 1 alpha), an endoplasmic reticulum (ER) resident transmembrane protein. In silico docking analysis and biochemical assays using recombinant human IRE1α confirm the binding of kaempferol to the ATP binding site of IRE1α, which thereby activates IRE1α ribonuclease activity. Treatment of cells with the small molecule STF083010, which specifically targets and inhibits the endoribonuclease activity of IRE1α, showed reduced expression of neuron-specific markers and curtailed neuritogenesis. The knockdown of IRE1α using plasmid-based shRNA lentiviral particles also showed diminished changes in the morphology of the cells upon kaempferol treatment. Thus, our study suggests that kaempferol induces differentiation of neuroblastoma cells via the IRE1α -XBP1 pathway. This article is protected by copyright. All rights reserved.
    Keywords:  IRE1α; Kaempferol; Neuroblastoma; Neuronal differentiation; XBP1
    DOI:  https://doi.org/10.1111/febs.14776
  7. Oncotarget. 2019 Jan 08. 10(3): 368-382
    ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).
    Sylvia Moeckel, Kelly LaFrance, Julia Wetsch, Corinna Seliger, Markus J Riemenschneider, Martin Proescholdt, Peter Hau, Arabel Vollmann-Zwerenz.
      Receptor tyrosine kinase (RTK) pathways are known to play an important role in tumor cell proliferation of glioblastoma (GBM). Cellular determinants of RTK-inhibitor sensitivity are important to optimize and tailor treatment strategies. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, little is known about its function in GBM. We found that the ATF4/p-eIF2α pathway is activated in response to Sunitinib in primary tumor initiating progenitor cell cultures (BTICs). Furthermore, lysosome entrapment of RTK-inhibitors (RTK-Is) leads to accumulation of autophagosomes. In case of Sunitinib treated cells, autophagy is additionally increased by ATF4 mediated upregulation of autophagy genes. Inhibition of ATF4 by small interfering RNA (siRNA) reduced autophagy and cell proliferation after Sunitinib treatment in a subset of BTIC cultures. Overall, this study suggests a pro-survival role of the ATF4/p-eIF2α pathway in a cell type and treatment specific manner.
    Keywords:  ATF4; brain tumor initiating cells; glioblastoma; receptor-tyrosine-kinase-inhibitor; therapy resistance
    DOI:  https://doi.org/10.18632/oncotarget.26569
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