bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒12‒01
thirteen papers selected by
Susan Logue
University of Manitoba
  1. The impact of endoplasmic reticulum stress responses in dendritic cell immunobiology.
  2. The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.
  3. Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy.
  4. FOXD3, frequently methylated in colorectal cancer, acts as a tumor suppressor and induces tumor cell apoptosis under ER stress via p53.
  5. Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress.
  6. Reduced expression of proteolipid protein 2 increases ER stress-induced apoptosis and autophagy in glioblastoma.
  7. Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors.
  8. Saved by the Matrix: UPR Independent Survival under ER Stress.
  9. Multiple system-level feedback loops control life-and-death decisions in endoplasmic reticulum stress.
  10. Cell Surface GRP78 as a Death Receptor and an Anticancer Drug Target.
  11. Endoplasmic Reticulum Stress and Autophagy.
  12. eIF2α-CHOP-BCl-2/JNK and IRE1α-XBP1/JNK signaling promote apoptosis and inflammation and support the proliferation of Newcastle disease virus.
  13. Endoplasmic Reticulum Stress Cooperates in Silica Nanoparticles-Induced Macrophage Apoptosis via Activation of CHOP-Mediated Apoptotic Signaling Pathway.
  1. Int Rev Cell Mol Biol. 2019 ;pii: S1937-6448(19)30075-9. [Epub ahead of print]349 153-176
    The impact of endoplasmic reticulum stress responses in dendritic cell immunobiology.
    Camilla Salvagno, Juan R Cubillos-Ruiz.
      Dendritic cells (DCs) are critical for bridging innate and adaptive immunity. They do so by presenting antigens to T cells, and by expressing diverse molecules that further promote T cell activation, differentiation and memory formation. During this process, intracellular and extracellular factors can perturb the protein-folding capacity of endoplasmic reticulum (ER) and induce a cellular state of "ER stress," which is controlled and resolved by the unfolded protein response (UPR). Interestingly, various studies have shown that DCs can activate UPR-related pathways even in the absence of global ER stress, and that this process can modulate their normal activity. In other settings, such as cancer, adverse microenvironmental conditions have been demonstrated to evoke severe ER stress and persistent activation of the UPR in tumor-infiltrating DCs. This process disrupts their metabolism and local antigen-presenting capacity, hence impeding the initiation and maintenance of anti-cancer immunity. Here, we review recent findings on how canonical and non-canonical UPR activation impacts DC immunobiology at the steady-state, upon activation via pattern recognition receptors, and under diverse pathological conditions. We also discuss the potential therapeutic implications that targeting the UPR in DCs may have in the context of cancer and in other pathologies such as graft-versus-host disease.
    Keywords:  Dendritic cells; ER stress; IRE1; Immunobiology; PERK; Unfolded protein response; XBP1
    DOI:  https://doi.org/10.1016/bs.ircmb.2019.08.004
  2. Cell. 2019 Nov 27. pii: S0092-8674(19)31168-7. [Epub ahead of print]179(6): 1306-1318.e18
    The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.
    Robert Thomas Schinzel, Ryo Higuchi-Sanabria, Ophir Shalem, Erica Ann Moehle, Brant Michael Webster, Larry Joe, Raz Bar-Ziv, Phillip Andrew Frankino, Jenni Durieux, Corinne Pender, Naame Kelet, Saranya Santhosh Kumar, Nupur Savalia, Hannah Chi, Milos Simic, Ngoc-Tram Nguyen, Andrew Dillin.
      Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.
    Keywords:  CRISPR-Cas9; MAPK signaling; aging; endoplasmic reticulum; extracellular matrix; glucosaminoglycan; immune response; stress response
    DOI:  https://doi.org/10.1016/j.cell.2019.10.018
  3. Cell Death Dis. 2019 Nov 25. 10(12): 887
    Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy.
    Di Wang, Peiran Zhang, Xiaolong Xu, Jianhui Wang, Dong Wang, Pandi Peng, Chao Zheng, Qing-Jun Meng, Liu Yang, Zhuojing Luo.
      Chordoma is a malignant primary osseous spinal tumor with pronounced chemoresistance. However, the mechanisms of how chordoma cells develop chemoresistance are still not fully understood. Cytokeratin 8 (KRT8) is a molecular marker of notochordal cells, from which chordoma cells were believed to be originated. In this study, we showed that either doxorubicin or irinotecan promoted KRT8 expression in both CM319 and UCH1 cell lines, accompanied by an increased unfolded protein response and autophagy activity. Then, siRNA-mediated knockdown of KRT8 chemosensitized chordoma cells in vitro. Mechanistic studies showed that knockdown of KRT8 followed by chemotherapy aggravated endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocked late-stage autophagy. Moreover, suppression of the PERK/eIF2α arm of unfolded protein response using PERK inhibitor GSK2606414 partially rescued the apoptotic chordoma cells but did not reverse the blockage of the autophagy flux. Finally, tumor xenograft model further confirmed the chemosensitizing effects of siKRT8. This study represents the first systematic investigation into the role of KRT8 in chemoresistance of chordoma and our results highlight a possible strategy of targeting KRT8 to overcome chordoma chemoresistance.
    DOI:  https://doi.org/10.1038/s41419-019-2125-9
  4. Carcinogenesis. 2019 Nov 30. pii: bgz198. [Epub ahead of print]
    FOXD3, frequently methylated in colorectal cancer, acts as a tumor suppressor and induces tumor cell apoptosis under ER stress via p53.
    Ming Xu, Jing Zhu, Shuiping Liu, Chan Wang, Qinglan Shi, Yeye Kuang, Xiao Fang, Xiaotong Hu.
      Forkhead box D3 (FOXD3), an important member of the forkhead box transcription factor family, has many biological functions. However, the role and signaling pathways of FOXD3 in colorectal cancer (CRC) are still unclear. We examined FOXD3 expression and methylation in normal colon mucosa, CRC cell lines, and primary tumors by RT-PCR, methylation-specific PCR, and bisulfite genomic sequencing. We also evaluated its tumor-suppressive function by examining its modulation of apoptosis under endoplasmic reticulum (ER) stress in CRC cells. The FOXD3 target signal pathway was identified by western blotting, immunofluorescence, and chromatin immunoprecipitation. We found that FOXD3 was frequently methylated and silenced in CRC cell lines and was downregulated in CRC tissues compared with paired adjacent non-tumor tissues. Meanwhile, low FOXD3 protein expression was significantly correlated with poor histopathological grading, lymph node metastasis, and poor prognosis of patients, indicating its potential as a tumor marker that may be of potential value as a therapeutic target for CRC. Moreover, restoration of FOXD3 expression inhibited the proliferation and migration of tumor cells. FOXD3 also increased mitochondrial apoptosis through the unfolded protein response under ER stress. Furthermore, we found that FOXD3 could bind directly to the promoter of p53 and enhance its expression. Knockdown of p53 impaired the effect of apoptosis induced by FOXD3. In conclusion, we showed for the first time that FOXD3, which is frequently methylated in CRC, acted as a tumor suppressor inducing tumor cell apoptosis under ER stress via p53.
    Keywords:  ER stress; FOXD3; apoptosis; methylation; p53
    DOI:  https://doi.org/10.1093/carcin/bgz198
  5. FEBS J. 2019 Nov 24.
    Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress.
    Sinem Tunçer, Aslı Sade-Memişoğlu, Ayşe Gökçe Keşküş, Ilir Sheraj, Güneş Güner, Aytekin Akyol, Sreeparna Banerjee.
      Intestinal epithelial cells are derived from stem cells at the crypts that undergo differentiation into transit amplifying cells, which in turn form terminally differentiated enterocytes as these cells reach the villus. Extensive alterations in both transcriptional and translational programs occur during differentiation, which can induce the activation of cellular stress responses such as Endosplasmic Reticulum (ER) stress related unfolded protein response (UPR) and autophagy, particularly in the cells that are already committed to becoming absorptive cells. Using an epithelial cell model of enterocyte differentiation, we report a mechanistic study connecting enterocyte differentiation to UPR and autophagy. We report that differentiated colon epithelial cells showed increased cytosolic Ca2+ levels and activation of all three pathways of UPR: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Activating Transcription Factor 6 (ATF6) compared to the undifferentiated cells. Enhanced UPR in the differentiated cells was accompanied by the induction of autophagy as evidenced by increased ratio of LC3 II/I, upregulation of Beclin-1 and downregulation of p62. We show for the first time that mechanistically, the upregulation of Hepatocyte Nuclear Factor 4α (HNF4α) during differentiation led to increased promoter binding and transcriptional upregulation of two major proteins of UPR: X-box binding protein-1 (XBP1) and ATF6, implicating HNF4α as a key regulator of UPR response during differentiation. Integrating wet-lab with in silico analyses, the present study links differentiation to cellular stress responses, and highlights the importance of transcription factor signaling and cross-talk between the cellular events in the regulation of intestinal cell differentiation.
    Keywords:  ATF6; Colon; ER stress; HNF4α; XBP1; autophagy; differentiation
    DOI:  https://doi.org/10.1111/febs.15152
  6. J Cell Mol Med. 2019 Nov 28.
    Reduced expression of proteolipid protein 2 increases ER stress-induced apoptosis and autophagy in glioblastoma.
    Zichao Feng, Wenjing Zhou, Jiwei Wang, Qichao Qi, Mingzhi Han, Yang Kong, Yaotian Hu, Yulin Zhang, Anbin Chen, Bin Huang, Anjing Chen, Di Zhang, Wenjie Li, Qing Zhang, Rolf Bjerkvig, Jian Wang, Frits Thorsen, Xingang Li.
      Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be highly expressed in many cancer types, but its importance in glioma progression is poorly understood. Using publicly available datasets (Rembrandt, TCGA and CGGA), we found that the expression of PLP2 was significantly higher in high-grade gliomas than in low-grade gliomas. We confirmed these results at the protein level through IHC staining of high-grade (n = 56) and low-grade glioma biopsies (n = 16). Kaplan-Meier analysis demonstrated that increased PLP2 expression was associated with poorer patient survival. In functional experiments, siRNA and shRNA PLP2 knockdown induced ER stress and increased apoptosis and autophagy in U87 and U251 glioma cell lines. Inhibition of autophagy with chloroquine augmented apoptotic cell death in U87- and U251-siPLP2 cells. Finally, intracranial xenografts derived from U87- and U251-shPLP2 cells revealed that loss of PLP2 reduced glioma growth in vivo. Our results therefore indicate that increased PLP2 expression promotes GBM growth and that PLP2 represents a potential future therapeutic target.
    Keywords:  ER stress; apoptosis; autophagy; glioblastoma; proteolipid protein 2
    DOI:  https://doi.org/10.1111/jcmm.14840
  7. Cells. 2019 Nov 26. pii: E1514. [Epub ahead of print]8(12):
    Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors.
    Katie E Hurst, Kiley A Lawrence, Lety Reyes Angeles, Zhiwei Ye, Jie Zhang, Danyelle M Townsend, Nathan Dolloff, Jessica E Thaxton.
      Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.
    Keywords:  ER stress; T cell; immunotherapy; protein disulfide isomerase; redox; tumor cell; ubiquitin; unfolded protein response
    DOI:  https://doi.org/10.3390/cells8121514
  8. Cell. 2019 Nov 27. pii: S0092-8674(19)31268-1. [Epub ahead of print]179(6): 1246-1248
    Saved by the Matrix: UPR Independent Survival under ER Stress.
    Mandy Koopman, Claudio Hetz, Ellen A A Nollen.
      Cells are protected from endoplasmic reticulum stress through the unfolded protein response (UPR). In this issue of Cell, Schinzel, Higuchi-Sanabria, Shalem et al., identify a mechanism that helps cells cope with ER stress but is independent of canonical UPR activation, instead involving the extracellular matrix hyaluronidase, TMEM2, as a signaling mediator.
    DOI:  https://doi.org/10.1016/j.cell.2019.11.012
  9. FEBS Lett. 2019 Nov 26.
    Multiple system-level feedback loops control life-and-death decisions in endoplasmic reticulum stress.
    Orsolya Kapuy, Margita Márton, Gábor Bánhegyi, Vinod Pk.
      Scientific results have revealed that autophagy is able to promote cell survival in response to endoplasmic reticulum (ER) stress while drastic events result in apoptotic cell death. Here, we analyse the important crosstalk of life-and-death decisions from a systems biological perspective by studying the regulatory modules of the unfolded protein response (UPR). While a double negative loop between autophagy and apoptosis inducers is crucial for the switch-like characteristic of the stress response mechanism, a positive feedback loop between ER stress sensors is also essential. Corresponding to experimental data, here, we show the dynamical significance of Gadd34-CHOP connections inside the PERK branch of the UPR. The multiple system-level feedback loops seem to be crucial for managing a robust life-and-death decision depending on the level and durability of cellular stress.
    Keywords:  apoptosis; autophagy; endoplasmic reticulum stress; feedback loops; systems biology
    DOI:  https://doi.org/10.1002/1873-3468.13689
  10. Cancers (Basel). 2019 Nov 13. pii: E1787. [Epub ahead of print]11(11):
    Cell Surface GRP78 as a Death Receptor and an Anticancer Drug Target.
    Ruowen Ge, Chieh Kao.
      Cell surface GRP78 (csGRP78, glucose-regulated protein 78 kDa) is preferentially overexpressed in aggressive, metastatic, and chemo-resistant cancers. GRP78 is best studied as a chaperone protein in the lumen of endoplasmic reticulum (ER), facilitating folding and secretion of the newly synthesized proteins and regulating protein degradation as an ER stress sensor in the unfolded protein pathway. As a cell surface signal receptor, multiple csGRP78 ligands have been discovered to date, and they trigger various downstream cell signaling pathways including pro-proliferative, pro-survival, and pro-apoptotic pathways. In this perspective, we evaluate csGRP78 as a cell surface death receptor and its prospect as an anticancer drug target. The pro-apoptotic ligands of csGRP78 discovered so far include natural proteins, monoclonal antibodies, and synthetic peptides. Even the secreted GRP78 itself was recently found to function as a pro-apoptotic ligand for csGRP78, mediating pancreatic β-cell death. As csGRP78 is found to mainly configur as an external peripheral protein on cancer cell surface, how it can transmit death signals to the cytoplasmic environment remains enigmatic. With the recent encouraging results from the natural csGRP78 targeting pro-apoptotic monoclonal antibody PAT-SM6 in early-stage cancer clinical trials, the potential to develop a novel class of anticancer therapeutics targeting csGRP78 is becoming more compelling.
    Keywords:  anticancer drug; apoptosis; cell surface GRP78 (csGRP78); death receptor
    DOI:  https://doi.org/10.3390/cancers11111787
  11. Adv Exp Med Biol. 2019 ;1206 167-177
    Endoplasmic Reticulum Stress and Autophagy.
    Zhihao Qi, Linxi Chen.
      In 1945, K. R. Porter et al. observed mouse embryonic fibroblasts (MEFs) and found that the cytoplasmic part of the cell had an unreported reticular structure, so it was named endoplasmic reticulum (ER). The major functions of the endoplasmic reticulum are: synthesis of intracellular proteins and the modification and processing of proteins. It is an important organelle in eukaryotic cells. It is a three-dimensional network structure in which complex and closed intracellular tubular intimal systems are intertwined. When cells are subjected to various strong stimulating factors such as nutrient deficiencies, Ca2+ metabolic imbalance, toxin stimulation, and sustained oxidative stress stimulation, the cell homeostasis will be broken. In order to survive, a series of cell self-protection event will be initiated including the endoplasmic reticulum stress (ERS). The UPR can further promote the expression of the proteins which can help the misfolded and unfolded proteins restore to its normal structure through the activation of PERK, IRE1, and ATF6. However, the co-working of UPR and the ubiquitin-proteasome system still cannot make the endoplasmic reticulum restoring to its normal state, when the stimuli persist or are too strong. The damaged endoplasmic reticulum can be partially engulfed by the autophagic vesicles for degradation when the ERS persists. The degraded endoplasmic reticulum fragments can be reassembled into a new endoplasmic reticulum to restore the normal state of it. Hence, it seems that the autophagy has become the last mean to restore the homeostasis of endoplasmic reticulum.
    Keywords:  Autophagy; Endoplasmic reticulum stress; The endoplasmic reticulum-associated degradation; Unfolded protein response
    DOI:  https://doi.org/10.1007/978-981-15-0602-4_8
  12. Cell Death Dis. 2019 Nov 26. 10(12): 891
    eIF2α-CHOP-BCl-2/JNK and IRE1α-XBP1/JNK signaling promote apoptosis and inflammation and support the proliferation of Newcastle disease virus.
    Yanrong Li, Weiyu Jiang, Qiaona Niu, Yingjie Sun, Chunchun Meng, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Chan Ding.
      Newcastle disease virus (NDV) causes severe infectious disease in poultry and selectively kills tumor cells, by inducing apoptosis and cytokines secretion. In this report, we study the mechanisms underlying NDV-induced apoptosis by investigating the unfolded protein response (UPR). We found that NDV infection activated all three branches of the UPR signaling (PERK-eIF2α, ATF6, and IRE1α) and triggered apoptosis, in avian cells (DF-1 and CEF) and in various human cancer cell types (HeLa, Cal27, HN13, A549, H1299, Huh7, and HepG2). Interestingly, the suppression of either apoptosis or UPR led to impaired NDV proliferation. Meanwhile, the inhibition of UPR by 4-PBA protected cells from NDV-induced apoptosis. Further study revealed that activation of PERK-eIF2α induced the expression of transcription factor CHOP, which subsequently promoted apoptosis by downregulating BCL-2/MCL-1, promoting JNK signaling and suppressing AKT signaling. In parallel, IRE1α mediated the splicing of XBP1 mRNA and resulted in the translation and nuclear translocation of XBP1s, thereby promoting the transcription of ER chaperones and components of ER-associated degradation (ERAD). Furthermore, IRE1α promoted apoptosis and cytokines secretion via the activation of JNK signaling. Knock down and overexpression studies showed that CHOP, IRE1α, XBP1, and JNK supported efficient virus proliferation. Our study demonstrates that the induction of eIF2α-CHOP-BCL-2/JNK and IRE1α-XBP1/JNK signaling cascades promote apoptosis and cytokines secretion, and these signaling cascades support NDV proliferation.
    DOI:  https://doi.org/10.1038/s41419-019-2128-6
  13. Int J Mol Sci. 2019 Nov 21. pii: E5846. [Epub ahead of print]20(23):
    Endoplasmic Reticulum Stress Cooperates in Silica Nanoparticles-Induced Macrophage Apoptosis via Activation of CHOP-Mediated Apoptotic Signaling Pathway.
    Fenglei Chen, Jiaqi Jin, Jiahui Hu, Yujing Wang, Zhiyu Ma, Jinlong Zhang.
      While silica nanoparticles (SiNPs) have wide applications, they inevitably increase atmospheric particulate matter and human exposure to this nanomaterial. Numerous studies have focused on how to disclose SiNP toxicity and on understanding its toxic mechanisms. However, there are few studies in the literature reporting the interaction between endoplasmic reticulum (ER) stress and SiNP exposure, and the corresponding detailed mechanisms have not been clearly determined. In this study, CCK-8 and flow cytometry assays demonstrated that SiNPs gradually decreased cell viability and increased cell apoptosis in RAW 264.7 macrophage cells in dose- and time-dependent manners. Western blot analysis showed that SiNPs significantly activated ER stress by upregulating GRP78, CHOP, and ERO1α expression. Meanwhile, western blot analysis also showed that SiNPs activated the mitochondrial-mediated apoptotic signaling pathway by upregulating BAD and Caspase-3, and downregulating the BCL-2/BAX ratio. Moreover, 4-phenylbutyrate (4-PBA), an ER stress inhibitor, significantly decreased GRP78, CHOP, and ERO1α expression, and inhibited cell apoptosis in RAW 264.7 macrophage cells. Furthermore, overexpression of CHOP significantly enhanced cell apoptosis, while knockdown of CHOP significantly protected RAW 264.7 macrophage cells from apoptosis induced by SiNPs. We found that the CHOP-ERO1α-caspase-dependent apoptotic signaling pathway was activated by upregulating the downstream target protein ERO1α and caspase-dependent mitochondrial-mediated apoptotic signaling pathway by upregulating Caspase-3 and downregulating the ratio of BCL-2/BAX. In summary, ER stress participated in cell apoptosis induced by SiNPs and CHOP regulated SiNP-induced cell apoptosis, at least partly, via activation of the CHOP-ERO1α-caspase apoptotic signaling pathway in RAW 264.7 macrophage cells.
    Keywords:  CHOP; apoptosis; endoplasmic reticulum stress; silica nanoparticles
    DOI:  https://doi.org/10.3390/ijms20235846
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