bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒07‒05
ten papers selected by
Susan Logue
University of Manitoba


  1. Autophagy. 2020 Jun 28.
    Zhang Z, Qian Q, Li M, Shao F, Ding WX, Lira VA, Chen SX, Sebag SC, Hotamisligil GS, Cao H, Yang L.
      Defective macroautophagy/autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, whether and how unresolved ER stress leads to defects in the autophagy pathway and to the progression of obesity-associated hepatic pathologies remains unclear. Obesity suppresses the expression of hepatic spliced XBP1 (X-box binding protein 1; sXBP1), the key transcription factor that promotes the adaptive UPR. Our RNA-seq analysis revealed that sXBP1 regulates genes involved in lysosomal function in the liver under fasting conditions. Chromatin immunoprecipitation (ChIP) analyses of both primary hepatocytes and whole liver further showed that sXBP1 occupies the -743 to -523 site of the promoter of Tfeb (transcription factor EB), a master regulator of autophagy and lysosome biogenesis. Notably, this occupancy was significantly reduced in livers from patients with steatosis. In mice, hepatic deletion of Xbp1 (xbp1 LKO) suppressed the transcription of Tfeb as well as autophagy, whereas hepatic overexpression of sXbp1 enhanced Tfeb transcription and autophagy. Moreover, overexpression of Tfeb in the xbp1 LKO mouse liver ameliorated glucose intolerance and steatosis in mice with diet-induced obesity (DIO). Conversely, loss of TFEB function impaired the protective role of sXBP1 in hepatic steatosis in mice with DIO. These data indicate that sXBP1-Tfeb signaling has direct functional consequences in the context of obesity. Collectively, our data provide novel insight into how two organelle stress responses are integrated to protect against obesity-associated metabolic dysfunction.
    Keywords:  autophagy; endoplasmic reticulum; liver; obesity; spliced X-box-binding protein 1; transcription factor EB
    DOI:  https://doi.org/10.1080/15548627.2020.1788889
  2. Cell Signal. 2020 Jun 25. pii: S0898-6568(20)30176-5. [Epub ahead of print]73 109699
    Kubra KT, Akhter MS, Uddin MA, Barabutis N.
      The unfolded protein response (UPR) is a highly conserved molecular machinery, which protects the cells against a diverse variety of stimuli. Activation of this element has been associated with both human health and disease. The purpose of the current manuscript is to provide the most updated information on the involvement of UPR towards the improvement; or deterioration of cardiovascular functions. Since UPR is consisted of three distinct elements, namely the activating transcription factor 6, the protein kinase RNA-like endoplasmic reticulum kinase; and the inositol-requiring enzyme-1α, a highly orchestrated manipulation of those molecular branches may provide new therapeutic possibilities against the severe outcomes of cardiovascular disease.
    Keywords:  Arrhythmia; Cardiac hypertrophy; ER stress; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.cellsig.2020.109699
  3. Chem Soc Rev. 2020 Jun 29.
    King AP, Wilson JJ.
      The endoplasmic reticulum (ER) has recently emerged as a promising target for anticancer agents. Cytotoxic compounds that target the ER often exhibit selectivity for cancer cells over non-cancer cells. Furthermore, the induction of ER stress often leads to immunogenic cell death, providing another factor that contributes to the clinical efficacy of drugs that target this organelle. Among potential ER stress-inducing agents, metal complexes, which possess redox activity and modular structures, have arisen as promising candidates. In the last two decades, dozens of metal complexes have been reported that kill cancer cells via ER stress induction, and many of these complexes exhibit nanomolar activity in vitro as well as powerful tumor inhibition in vivo. In this review, we summarize the current state of investigations on the ER stress-inducing properties of metal complexes. This review starts with a description of the ER, its function, and its role in cancer progression and treatment. Following this discussion, a guide to experimental methods that can be used by researchers to detect ER stress is provided. The majority of this review summarizes previous studies on metal-based anticancer agents that cause ER stress. Finally, a discussion on the perspectives and significance of using metal complexes as ER stress-inducing agents for the treatment of cancer is provided, along with a summary of structural trends that contribute to this type of biological activity.
    DOI:  https://doi.org/10.1039/d0cs00259c
  4. BMC Biol. 2020 Jun 29. 18(1): 74
    Tjahjono E, McAnena AP, Kirienko NV.
      BACKGROUND: Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Cells actively surveil a number of mitochondrial readouts to ensure that cellular homeostasis is maintained.RESULTS: In this article, we characterize the role of the ethanol and stress response element (ESRE) pathway in mitochondrial surveillance and show that it is robustly activated when the concentration of reactive oxygen species (ROS) in the cell increases. While experiments were mostly performed in Caenorhabditis elegans, we observed similar gene activation profile in human cell lines. The linear relationship between ROS and ESRE activation differentiates ESRE from known mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt), which monitor mitochondrial protein import. The ability of the ESRE network to be activated by increased ROS allows the cell to respond to oxidative and reductive stresses. The ESRE network works in tandem with other mitochondrial surveillance mechanisms as well, in a fashion that suggests a partially redundant hierarchy. For example, mutation of the UPRmt pathway results in earlier and more robust activation of the ESRE pathway. Interestingly, full expression of ATFS-1, a key transcription factor for the UPRmt, requires the presence of an ESRE motif in its promoter region.
    CONCLUSION: The ESRE pathway responds to mitochondrial damage by monitoring ROS levels. This response is conserved in humans. The ESRE pathway is activated earlier when other mitochondrial surveillance pathways are unavailable during mitochondrial crises, potentially to mitigate stress and restore health. However, the exact mechanisms of pathway activation and crosstalk remain to be elucidated. Ultimately, a better understanding of this network, and its role in the constellation of mitochondrial and cellular stress networks, will improve healthspan.
    Keywords:  ESRE; Mitochondria; Reductive stress; Superoxide; Surveillance; UPRmt
    DOI:  https://doi.org/10.1186/s12915-020-00812-5
  5. Sci Rep. 2020 Jul 03. 10(1): 10986
    White SA, Zhang LS, Pasula DJ, Yang YHC, Luciani DS.
      ER stress and apoptosis contribute to the loss of pancreatic β-cells under pro-diabetic conditions of glucolipotoxicity. Although activation of canonical intrinsic apoptosis is known to require pro-apoptotic Bcl-2 family proteins Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death are not known. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro occurs by both non-apoptotic and apoptotic mechanisms, and the apoptosis could be triggered by either Bax or Bak alone. In contrast, they had non-redundant roles in mediating staurosporine-induced apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that combined deletion of Bax and Bak amplified the unfolded protein response in islets during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings shed new light on roles of the core apoptosis machinery in β-cell survival and stress signals of importance for the pathobiology of diabetes.
    DOI:  https://doi.org/10.1038/s41598-020-67755-3
  6. Genes Dev. 2020 Jul 02.
    Longman D, Jackson-Jones KA, Maslon MM, Murphy LC, Young RS, Stoddart JJ, Hug N, Taylor MS, Papadopoulos DK, Cáceres JF.
      Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking, as a novel NMD factor. Furthermore, we show that NBAS fulfills an independent function in NMD. This ER-NMD pathway requires the interaction of NBAS with the core NMD factor UPF1, which is partially localized at the ER in the proximity of the translocon. NBAS and UPF1 coregulate the stability of ER-associated transcripts, in particular those associated with the cellular stress response. We propose a model where NBAS recruits UPF1 to the membrane of the ER and activates an ER-dedicated NMD pathway, thus providing an ER-protective function by ensuring quality control of ER-translated mRNAs.
    Keywords:  ER stress; NBAS; RNA quality control; UPF1; UPR; nonsense-mediated decay (NMD)
    DOI:  https://doi.org/10.1101/gad.338061.120
  7. Drug Resist Updat. 2020 May 18. pii: S1368-7646(20)30032-7. [Epub ahead of print]52 100703
    Long L, Assaraf YG, Lei ZN, Peng H, Yang L, Chen ZS, Ren S.
      Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with complex heterogenous genetic and biological nature. Thus, prognostic prediction and targeted therapies might contribute to better chemotherapeutic response. However, the emergence of multidrug resistance (MDR) markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Therefore, prior evaluation of chemoresistance is of great importance in therapeutic decision making and prognosis. In recent years, preclinical studies on chemoresistance have unveiled a compendium of underlying molecular basis, which facilitated the development of targetable small molecules. Furthermore, routing genomic sequencing has identified various genomic aberrations driving cellular response during the course of therapeutic treatment through adaptive mechanisms of drug resistance, some of which serve as prognostic biomarkers in risk stratification. However, the underlying mechanisms of MDR have challenged the certainty of the prognostic significance of some mutations. This review aims to provide a comprehensive understanding of the role of MDR in therapeutic decision making and prognostic prediction in AML. We present an updated genetic landscape of the predominant mechanisms of drug resistance with novel targeted therapies and potential prognostic biomarkers from preclinical and clinical chemoresistance studies in AML. We particularly highlight the unfolded protein response (UPR) that has emerged as a critical regulatory pathway in chemoresistance of AML with promising therapeutic horizon. Futhermore, we outline the most prevalent mutations associated with mechanisms of chemoresistance and delineate the future directions to improve the current prognostic tools. The molecular analysis of chemoresistance integrated with genetic profiling will facilitate decision making towards personalized prognostic prediction and enhanced therapeutic efficacy.
    Keywords:  Acute myeloid leukemia; Biomarkers; Genetic mutations; Multidrug resistance; Prognosis
    DOI:  https://doi.org/10.1016/j.drup.2020.100703
  8. Breast Cancer Res Treat. 2020 Jun 29.
    Chen FM, Huang LJ, Ou-Yang F, Kan JY, Kao LC, Hou MF.
      PURPOSE: Mitochondrial unfolding protein are abundant in breast cancer cells, but the mechanism by which breast cancer cells resist apoptosis is still not fully elucidated. In this study, we explored the role of mitochondrial unfolded protein response (mtUPR)-related proteins in four types of breast cancer tissues.METHODS: Mitochondrial fractions were taken from four breast cancer tissues (luminal A, luminal B, Her2 -overexpression, and TNBC) and the expression of mitochondrial polyubiquitinated proteins was observed by western blot and ELISA. In addition, the expression of hsp10, hsp60, and clpp in mitochondria was observed by western blot in breast cancer tissues and adjacent tissues, and confirmed by ELISA. The expression levels of hsp10 and hsp60 were correlated with clinicopathological parameters in 114 breast cancer patients.
    RESULTS: We found an increase in the performance of mitochondrial polyubiquitinated proteins in breast cancer tissues of luminal A, luminal B, Her2-overexpression, and TNBC. The mitochondrial hsp10, hsp60, and clpp are abundantly expressed in breast cancer tissues rather than adjacent noncancerous tissues. The expression levels of mitochondrial hsp10 and hsp60 were highest in histological grade 3 breast cancer tissues. Additionally, mitochondria with high hsp60 expression were more present in Her2-positive tumors.
    CONCLUSIONS: We observed that mtUPR was specifically activated in breast cancer tissues but inactivated in normal mammary tissue. MtUPR had also exhibited a particular increase in Her2-overexpression tumors but not in ER- or PR-positive tumors. Taken together, we suggested that mtUPR may act as a potential candidate for developing novel Her2-overexpression breast cancer therapy.
    Keywords:  Breast cancer‧mitochondrial unfolded protein response; Her2-overexpression; mtUPR
    DOI:  https://doi.org/10.1007/s10549-020-05729-9
  9. Cancers (Basel). 2020 Jun 26. pii: E1702. [Epub ahead of print]12(6):
    Wang YY, Lee KT, Lim MC, Choi JH.
      In addition to their analgesic activity, transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists demonstrate profound anti-cancer activities in various human cancers. In the present study, we investigated the anti-cancer activity of a novel TRPV1 antagonist, DWP05195, and evaluated its molecular mechanism in human ovarian cancer cells. DWP05195 demonstrated potent growth inhibitory effects in all five ovarian cancer cell lines examined. DWP05195 induced apoptosis through the activation of caspase-3, -8, and -9. DWP05195 induced C/EBP homologous protein (CHOP) expression and endoplasmic reticulum (ER) stress. Sodium phenylbutyrate (4-PBA), an ER-stress inhibitor, and CHOP knockdown significantly suppressed DWP5195-induced cell death. DWP05195-enhanced CHOP expression stimulated intrinsic and extrinsic apoptotic pathways through the regulation of Bcl2-like11 (BIM), death receptor 4 (DR4), and DR5. DWP05195-induced cell death was associated with increased reactive oxygen species (ROS) levels and p38 pathway activation. Pre-treatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed DWP05195-induced CHOP expression and p38 activation. Inhibition of NADPH oxidase (NOX) through p47phox knockdown abolished DWP05195-induced CHOP expression and cell death. Taken together, the findings indicate that DWP05195 induces ER stress-induced apoptosis via the ROS-p38-CHOP pathway in human ovarian cancer cells.
    Keywords:  CHOP; DWP05195; ER stress; ROS; TRPV1 antagonist; ovarian cancer
    DOI:  https://doi.org/10.3390/cancers12061702