bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒01‒17
eleven papers selected by
Susan Logue
University of Manitoba

  1. Cancers (Basel). 2021 Jan 12. pii: E261. [Epub ahead of print]13(2):
      Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.
    Keywords:  activating transcription factor 6 (ATF6); endoplasmic reticulum (ER); inositol-requiring enzyme 1 (IRE1); protein kinase RNA-like ER kinase (PERK); unfolded protein response (UPR)
  2. Biomolecules. 2021 Jan 07. pii: E73. [Epub ahead of print]11(1):
      Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases.
    Keywords:  ER stress; kidney; lipogenesis
  3. Semin Cancer Biol. 2021 Jan 07. pii: S1044-579X(21)00002-X. [Epub ahead of print]
      The development of biological technologies in genomics, proteomics, and bioinformatics has led to the identification and characterization of the complete set of coding genes and their roles in various cellular pathways in cancer. Nevertheless, the cellular pathways have not been fully figured out like a jigsaw puzzle with missing pieces. The discovery of noncoding RNAs including microRNAs (miRNAs) has provided the missing pieces of the cellular pathways. Likewise, miRNAs have settled many questions of inexplicable patches in the endoplasmic reticulum (ER) stress pathways. The ER stress-caused pathways typified by the unfolded protein response (UPR) are pivotal processes for cellular homeostasis and survival, rectifying uncontrolled proteostasis and determining the cell fate. Although various factors and pathways have been studied and characterized, the understanding of the ER stress requires more wedges to fill the cracks of knowledge about the ER stress pathways. Moreover, the roles of the ER stress and UPR are still controversial in cancer despite their strong potential to promote cancer. The noncoding RNAs, in particular, miRNAs aid in a better understanding of the ER stress and its role in cancer. In this review, miRNAs that are the more-investigated subtype of noncoding RNAs are focused on the interpretation of the ER stress in cancer, following the introduction of miRNA and ER stress.
    Keywords:  Cancer; Cell death; Endoplasmic reticulum stress; Unfolded protein response; microRNA
  4. Front Oncol. 2020 ;10 598107
      N-acetyltransferase 10 (NAT10) has oncogenic properties in many tumors through its role in different cellular biological processes. NAT10 is also a potential biomarker in acute myeloid leukemia (AML); however, the mechanisms underlying NAT10's contribution to disease states and the effect of targeting NAT10 as a therapeutic target remain unclear. NAT10 was found to be highly expressed in patients with AML, and increased NAT10 expression was associated with poor outcomes. Additionally, targeting NAT10 via the shRNA knockdown and its pharmacotherapeutic inhibitor resulted in inhibition of cell proliferation, induction of cell cycle arrest in the G1 phase, and apoptosis in AML cells. Moreover, NAT10 induces cell cycle arrest by decreasing expression of CDK2, CDK4, CyclinD1, Cyclin E while simultaneously increasing the expression of p16 and p21. Targeting NAT10 induces ER stress through the increased expression of GRP78 and the cleavage of caspase 12, which are classical markers of ER stress. This triggered the Unfolded Protein Response (UPR) pathway by consequently increasing IRE1, CHOP, and PERK expression, all of which play crucial roles in the UPR pathway. Targeting NAT10 also activated the classical apoptotic pathway through the upregulation of the Bax/bak and the concurrent downregulation of Bcl-2. In summary, our data indicate that targeting NAT10 promotes ER stress, triggers the UPR pathway, and activates the Bax/Bcl-2 axis in AML cells. Our results thus indicate a novel mechanism underlying the induction of NAT10 inhibition-mediated apoptosis and reveal the potential for the therapeutic effect of a NAT10 specific inhibitor in AML.
    Keywords:  N-acetyltransferase; NAT10; acute myeloid leukemia; apoptosis; remodelin hydrobromide
  5. Oncotarget. 2020 Dec 29. 11(52): 4788-4802
      Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ12,14 prostamide J2 (15dPMJ2). As such, the current study investigates whether 15dPMJ2 induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ2 caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ2 also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ2 to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ2-treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ2-mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ2 and the ER stress pathway. These results demonstrate that 15dPMJ2 is a tumor-selective inducer of DAMP signaling in melanoma.
    Keywords:  calreticulin; dendritic cells; endocannabinoid metabolite; endoplasmic reticulum stress
  6. Redox Biol. 2021 Jan 06. pii: S2213-2317(21)00001-X. [Epub ahead of print]40 101853
      Chalcone is a polyphenolic compound found abundantly in natural plant components. They have been acclaimed as potential antitumor compounds in multiple tumor cells. However, not much attention has been paid to elucidate its antitumor mechanism of action. Here, chalcone was demonstrated to trigger endoplasmic reticulum (ER) stress-induced apoptosis through sulfonation of IRE1α by ER-localized NADPH oxidase 4 (NOX4). IRE1α-sulfonation at a cysteine residue was shown to induce "regulated IRE1α-dependent decay" (RIDD) of mRNA rather than specific splicing of XBP1. The IRE1α sulfonation-induced RIDD degraded miR-23b, enhancing the expression of NOX4. The expression of NOX4 was also upregulated in breast, and prostate cancer tissue. In chalcone-administered mice in vivo, tumor growth was regressed by the consistent mechanisms "NOX4-IRE1α sulfonation-RIDD". Similarly, NOX4 activation and IRE1α sulfonation were also highly increased under severe ER stress conditions. Together, these findings suggest chalcone as a lead anticancer compound where it acts through NOX4-IRE1α-RIDD-miR-23b axis providing a promising vision of chalcone derivatives' anticancer mechanism.
    Keywords:  Apoptosis; Chalcone; IRE1α sulfonation; NOX4; RIDD; miR-23b
  7. Cell Mol Life Sci. 2021 Jan 15.
      Biological oscillations often cycle at different harmonics of the 24-h circadian rhythms, a phenomenon we coined "Musica Universalis" in 2017. Like the circadian rhythm, the 12-h oscillation is also evolutionarily conserved, robust, and has recently gained new traction in the field of chronobiology. Originally thought to be regulated by the circadian clock and/or environmental cues, recent new evidences support the notion that the majority of 12-h rhythms are regulated by a distinct and cell-autonomous pacemaker that includes the unfolded protein response (UPR) transcription factor spliced form of XBP1 (XBP1s). 12-h cycle of XBP1s level in turn transcriptionally generates robust 12-h rhythms of gene expression enriched in the central dogma information flow (CEDIF) pathway. Given the regulatory and functional separation of the 12-h and circadian clocks, in this review, we will focus our attention on the mammalian 12-h pacemaker, and discuss our current understanding of its prevalence, evolutionary origin, regulation, and functional roles in both physiological and pathological processes.
    Keywords:  12-h clock; Circadian rhythm; ER stress; Ultradian rhythm; Unfolded protein response; XBP1s
  8. J Exp Clin Cancer Res. 2021 Jan 11. 40(1): 28
      Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.
    Keywords:  Chemoresistance; Endoplasmic reticulum stress; Hypoxia; Hypoxia-inducible factor-1α; Unfolded protein response
  9. Mol Biol Cell. 2021 Jan 15. 32(2): 109-119
      The endoplasmic reticulum (ER) is one of the largest cytoplasmic organelles in eukaryotic cells and plays a role in many cellular processes, such as the production and quality control of secretory protein, lipid synthesis, and calcium homeostasis. The ER cannot be generated de novo, and thus its proper inheritance during cell division is paramount to the health and survival of the daughter cells. Although previous work has uncovered the cytoskeletal components involved, we still lack a comprehensive understanding of the intricate steps of and the cytoplasmic and membrane-bound components involved in ER inheritance. To directly address these issues, we utilized microfluidics and genetic analyses to show that before nuclear migration, early ER inheritance can be further divided into three distinctive steps. Moreover, we demonstrated that perturbing each of these steps affects the cell's ability to mitigate ER stress. Thus, proper ER inheritance is essential to ensuring a healthy, functional cell.
  10. Sci Rep. 2021 Jan 11. 11(1): 393
      Zika virus (ZIKV) is a mosquito-transmitted virus that has caused significant public health concerns around the world, partly because of an association with microcephaly in babies born to mothers who were infected with ZIKV during pregnancy. As a recently emerging virus, little is known as to how the virus interacts with the host cell machinery. A yeast-2-hybrid screen for proteins capable of interacting with the ZIKV E protein domain III, the domain responsible for receptor binding, identified 21 proteins, one of which was the predominantly ER resident chaperone protein GRP78. The interaction of GRP78 and ZIKV E was confirmed by co-immunoprecipitation and reciprocal co-immunoprecipitation, and indirect immunofluorescence staining showed intracellular and extracellular co-localization between GRP78 and ZIKV E. Antibodies directed against the N-terminus of GRP78 were able to inhibit ZIKV entry to host cells, resulting in significant reductions in the levels of ZIKV infection and viral production. Consistently, these reductions were also observed after down-regulation of GRP78 by siRNA. These results indicate that GRP78 can play a role mediating ZIKV binding, internalization and replication in cells. GRP78 is a main regulator of the unfolded protein response (UPR), and the study showed that expression of GRP78 was up-regulated, and the UPR was activated. Increases in CHOP expression, and activation of caspases 7 and 9 were also shown in response to ZIKV infection. Overall these results indicate that the interaction between GRP78 and ZIKV E protein plays an important role in ZIKV infection and replication, and may be a potential therapeutic target.
  11. Exp Cell Res. 2021 Jan 09. pii: S0014-4827(21)00005-7. [Epub ahead of print] 112474
      The aging proteostasis decline manifests in a failure of aging cells and organisms to properly respond to proteotoxic challenges. This proteostasis collapse has long been considered a hallmark of aging in nematodes, and has recently been shown to occur also in human cells upon entry to senescence, opening the way to exploring the phenomenon in the broader context of human aging. Cellular senescence is part of the normal human physiology of aging, with senescent cell accumulation as a prominent feature of aged tissues. Being highly resistant to cell death, senescent cells, as they accumulate, become pro-inflammatory and promote disease. Here we discuss the causes of human senescence proteostasis decline, in view of the current literature on nematodes, on the one hand, and senescence, on the other hand. We review two major aspects of the phenomenon: (1) the decline in transcriptional activation of stress-response pathways, and (2) impairments in proteasome function. We further outline potential underlying mechanisms of transcriptional proteostasis decline, focusing on reduced chromatin dynamics and compromised nuclear integrity. Finally, we discuss potential strategies for reinforcing proteostasis as a means to improve organismal health and address the relationship to senolytics.
    Keywords:  ATF6; HSF1; HSR; Protein homeostasis; UPR; aging; heat shock response; proteostasis; senescence