bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–05–14
ten papers selected by
Susan Logue, University of Manitoba
  1. Activation of XBP1 but not ATF6α rescues heart failure induced by persistent ER stress in medaka fish.
  2. SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.
  3. Role of lncRNAs in hepatocellular carcinoma.
  4. Long noncoding RNA 01534 maintains cancer stemness by downregulating endoplasmic reticulum stress response in colorectal cancer.
  5. Molecular basis of the TRAP complex function in ER protein biogenesis.
  6. Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy.
  7. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.
  8. Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt.
  9. Pancreatic beta cell ER export in health and diabetes.
  10. Endoplasmic Reticulum Stress Promotes Prostate Cancer Cells to Release Exosome and Up-regulate PD-L1 Expression via PI3K/Akt Signaling Pathway in Macrophages.
  1. Life Sci Alliance. 2023 Jul;pii: e202201771. [Epub ahead of print]6(7):
    Activation of XBP1 but not ATF6α rescues heart failure induced by persistent ER stress in medaka fish.
    Byungseok Jin, Tokiro Ishikawa, Makoto Kashima, Rei Komura, Hiromi Hirata, Tetsuya Okada, Kazutoshi Mori.
      The unfolded protein response is triggered in vertebrates by ubiquitously expressed IRE1α/β (although IRE1β is gut-specific in mice), PERK, and ATF6α/β, transmembrane-type sensor proteins in the ER, to cope with ER stress, the accumulation of unfolded and misfolded proteins in the ER. Here, we burdened medaka fish, a vertebrate model organism, with ER stress persistently from fertilization by knocking out the AXER gene encoding an ATP/ADP exchanger in the ER membrane, leading to decreased ATP concentration-mediated impairment of the activity of Hsp70- and Hsp90-type molecular chaperones in the ER lumen. ER stress and apoptosis were evoked from 4 and 6 dpf, respectively, leading to the death of all AXER-KO medaka by 12 dpf because of heart failure (medaka hatch at 7 dpf). Importantly, constitutive activation of IRE1α signaling-but not ATF6α signaling-rescued this heart failure and allowed AXER-KO medaka to survive 3 d longer, likely because of XBP1-mediated transcriptional induction of ER-associated degradation components. Thus, activation of a specific pathway of the unfolded protein response can cure defects in a particular organ.
    DOI:  https://doi.org/10.26508/lsa.202201771
  2. bioRxiv. 2023 Apr 24. pii: 2023.04.22.537917. [Epub ahead of print]
    SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.
    Jonathan P Davies, Athira Sivadas, Katherine R Keller, Richard J H Wojcikiewicz, Lars Plate.
      Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis pathways during infection through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR). The UPR regulates protein translation, increases protein folding capacity and enhances endoplasmic reticulum (ER) biogenesis to alleviate ER stress caused by accumulation of misfolded proteins. CoVs depend on host machinery to generate large amounts of viral protein and manipulate ER-derived membranes to form double-membrane vesicles (DMVs), which serve as replication sites, making the UPR a key host pathway for CoVs to hijack. Despite the importance of CoV nonstructural proteins (nsps) in mediating replication, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, which is a key driver of DMV formation, on the UPR using quantitative proteomics. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological activation of the ATF6 pathway. To determine how nsp3.1 and nsp4 might tune the UPR in concert, both proteins were co-expressed demonstrating that nsp3.1 does not suppress nsp4-mediated ATF6 activation but does suppress PERK activation. A meta-analysis of SARS-CoV-2 infection proteomics data reveals a time-dependent activation of PERK protein markers early in infection, which subsequently fades. This temporal regulation suggests a role for nsps tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic PERK activation. This work furthers our understanding of CoV-host proteostasis interactions and identifies potential areas to target for anti-viral therapies.
    DOI:  https://doi.org/10.1101/2023.04.22.537917
  3. Life Sci. 2023 May 09. pii: S0024-3205(23)00385-5. [Epub ahead of print] 121751
    Role of lncRNAs in hepatocellular carcinoma.
    Smriti Verma, Bidhya Dhar Sahu, Madhav Nilakanth Mugale.
      Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies.
    Keywords:  Endoplasmic reticulum; Hepatocellular carcinoma; Long non-coding RNAs; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2023.121751
  4. Ann Gastroenterol Surg. 2023 May;7(3): 458-470
    Long noncoding RNA 01534 maintains cancer stemness by downregulating endoplasmic reticulum stress response in colorectal cancer.
    Momoko Ichihara, Hidekazu Takahashi, Naohiro Nishida, Cristina Ivan, Daisuke Okuzaki, Yuhki Yokoyama, Masahisa Ohtsuka, Norikatsu Miyoshi, Mamoru Uemura, Shinji Tanaka, George Adrian Calin, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hirofumi Yamamoto.
       Background: Studies have shown that cancer stemness and the endoplasmic reticulum (ER) stress response are inversely regulated in colorectal cancer (CRC), but the mechanism has not been fully clarified. Long noncoding RNAs (lncRNAs) play key roles in cancer progression and metastasis. In this study we investigated lncRNA 01534 (LINC01534) as a possible modulator between cancer stemness and ER stress response.
    Methods: In vitro experiments using CRC cell lines were performed to explore a possible role of LINC01534. The expression of LINC01534 in clinical CRC samples was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization.
    Results: Silencing LINC01534 led to suppression of cell proliferation, invasiveness, and cell cycle progression at the G2-M phase, and promoted apoptosis. Moreover, we found that silencing LINC01534 suppressed cancer stemness, while it activated the ER stress response, especially through the PERK/eIF2α signaling pathway. In situ hybridization revealed LINC01534 was expressed in tumor cells and upregulated in CRC tissues compared with normal epithelium. A survival survey indicated that high LINC01534 expression was significantly associated with shorter overall survival in 187 CRC patients.
    Conclusion: This is the first report on LINC01534 in human cancer. Our findings suggest that LINC01534 may be an important modulator of the maintenance of cancer stemness and suppression of the ER stress response, and that it could be a novel prognostic factor in CRC.
    Keywords:  LINC01534; cancer stemness; colorectal cancer; endoplasmic reticulum stress; long noncoding RNA
    DOI:  https://doi.org/10.1002/ags3.12649
  5. Nat Struct Mol Biol. 2023 May 11.
    Molecular basis of the TRAP complex function in ER protein biogenesis.
    Mateusz Jaskolowski, Ahmad Jomaa, Martin Gamerdinger, Sandeep Shrestha, Marc Leibundgut, Elke Deuerling, Nenad Ban.
      The translocon-associated protein (TRAP) complex resides in the endoplasmic reticulum (ER) membrane and interacts with the Sec translocon and the ribosome to facilitate biogenesis of secretory and membrane proteins. TRAP plays a key role in the secretion of many hormones, including insulin. Here we reveal the molecular architecture of the mammalian TRAP complex and how it engages the translating ribosome associated with Sec61 translocon on the ER membrane. The TRAP complex is anchored to the ribosome via a long tether and its position is further stabilized by a finger-like loop. This positions a cradle-like lumenal domain of TRAP below the translocon for interactions with translocated nascent chains. Our structure-guided TRAP mutations in Caenorhabditis elegans lead to growth deficits associated with increased ER stress and defects in protein hormone secretion. These findings elucidate the molecular basis of the TRAP complex in the biogenesis and translocation of proteins at the ER.
    DOI:  https://doi.org/10.1038/s41594-023-00990-0
  6. FASEB Bioadv. 2023 May;5(5): 211-220
    Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy.
    Amiee Dowdell, Mark Marsland, Sam Faulkner, Craig Gedye, James Lynam, Cassandra P Griffin, Joanne Marsland, Chen Chen Jiang, Hubert Hondermarck.
      Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x-box binding protein 1 (XBP1s) may constitute a novel therapeutic target; here we report XBP1s expression and biological activity in GBM. Tumor samples from patients with GBM (n = 85) and low-grade glioma (n = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low-grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient-derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC-3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O6-methylguanine-DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC-3946 and the long-term inhibitory effect of MKC-3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.
    Keywords:  XBP1s; cancer biomarkers; glioblastoma; therapeutic targets
    DOI:  https://doi.org/10.1096/fba.2022-00141
  7. Cell Commun Signal. 2023 May 08. 21(1): 102
    Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.
    Dong Lin, Yijia Chen, Ali Riza Koksal, Srikanta Dash, Yucel Aydin.
       BACKGROUND: Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed.
    METHODS: Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection.
    RESULTS: Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection.
    CONCLUSION: Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.
    Keywords:  Chronic hepatitis C virus (HCV) infection; Direct-acting antiviral agents (DAA); Endoplasmic reticulum stress (ER stress); Glycogen synthase kinase-3β (GSK-3β); Hepatocellular carcinoma (HCC); Protein kinase A (PKA); Wnt/β-catenin
    DOI:  https://doi.org/10.1186/s12964-023-01081-9
  8. Redox Biol. 2023 May 07. pii: S2213-2317(23)00123-4. [Epub ahead of print]63 102722
    Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt.
    Miaomiao Guo, Xinhua Qiao, Yuanyuan Wang, Zi-Han Li, Chang Shi, Yun Chen, Lu Kang, Chang Chen, Xiao-Long Zhou.
      Aminoacyl-tRNA synthetases (aaRSs) are indispensable players in translation. Usually, two or three genes encode cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs) in eukaryotes. Here, we reported that Caenorhabditis elegans harbors only one tars-1, generating cytoplasmic and mitochondrial ThrRSs via translational reinitiation. Mitochondrial tars-1 knockdown decreased mitochondrial tRNAThr charging and translation and caused pleotropic phenotypes of delayed development, decreased motor ability and prolonged lifespan, which could be rescued by replenishing mitochondrial tars-1. Mitochondrial tars-1 deficiency leads to compromised mitochondrial functions including the decrease in oxygen consumption rate, complex Ⅰ activity and the activation of the mitochondrial unfolded protein response (UPRmt), which contributes to longevity. Furthermore, deficiency of other eight mitochondrial aaRSs in C. elegans and five in mammal also caused activation of the UPRmt. In summary, we deciphered the mechanism of one tars-1, generating two aaRSs, and elucidated the biochemical features and physiological function of C. elegans tars-1. We further uncovered a conserved connection between mitochondrial translation deficiency and UPRmt.
    Keywords:  Aminoacyl-tRNA synthetases; Lifespan; Mitochondrial translation; UPR(mt); tars-1(ora1) Ⅱ/wt
    DOI:  https://doi.org/10.1016/j.redox.2023.102722
  9. Front Endocrinol (Lausanne). 2023 ;14 1155779
    Pancreatic beta cell ER export in health and diabetes.
    Cesar Barrabi, Kezhong Zhang, Ming Liu, Xuequn Chen.
      In the secretory pathway of the pancreatic beta cell, proinsulin and other secretory granule proteins are first produced in the endoplasmic reticulum (ER). Beta cell ER homeostasis is vital for normal beta cell functions and is maintained by the delicate balance between protein synthesis, folding, export and degradation. Disruption of ER homeostasis leads to beta cell death and diabetes. Among the four components to maintain ER homeostasis, the role of ER export in insulin biogenesis or beta cell survival was not well-understood. COPII (coat protein complex II) dependent transport is a conserved mechanism for most cargo proteins to exit ER and transport to Golgi apparatus. Emerging evidence began to reveal a critical role of COPII-dependent ER export in beta cells. In this review, we will first discuss the basic components of the COPII transport machinery, the regulation of cargo entry and COPII coat assembly in mammalian cells, and the general concept of receptor-mediated cargo sorting in COPII vesicles. On the basis of these general discussions, the current knowledge and recent developments specific to the beta cell COPII dependent ER export are summarized under normal and diabetic conditions.
    Keywords:  coat protein complex II (COPII); diabetes; endoplasmic reticulum (ER) export; pancreatic beta cells; proinsulin
    DOI:  https://doi.org/10.3389/fendo.2023.1155779
  10. J Cancer. 2023 ;14(6): 1062-1074
    Endoplasmic Reticulum Stress Promotes Prostate Cancer Cells to Release Exosome and Up-regulate PD-L1 Expression via PI3K/Akt Signaling Pathway in Macrophages.
    Wei Xu, Meiyi Lu, Siqi Xie, Dangui Zhou, Mei Zhu, Chaozhao Liang.
      Mounting evidence has demonstrated that endoplasmic reticulum stress (ERS) serves an important role in shaping the immunosuppressive microenvironment by modulating resident tumor-associated macrophages (TAMs). However, the communication between ER‑stressed tumor cells and TAMs is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress‑related exosomes in prostate cancer cells promoting macrophage infiltration and polarization, laser scanning confocal microscope, RT-PCR, flow cytometric analysis, western‑blotting and cytokine bead array analyses were performed.The results demonstrated that TG-EXO downregulated the expression of PD-L1 on macrophages through flow cytometry analysis. In addition, Compared with CON-EXO, the expression of macrophage-associated inflammatory cytokines IL-12, TNF-α and IL-1βwas significantly decreased in TG-EXO treatment (P< 0.05). TG-EXO upregulated the expression levels of IL-6, IL-10 and TGF-β cytokinesin macrophages. Our research shows that TG-EXO increased PI3K/AKT signaling pathway compared to the CON-EXO group. In summary, we found exosomes from TG-treated prostate cancer cells altered the immunosupression status and affected macrophages polarization by up-regulating the expression of PD-L1 and inflammatory factors and PI3K/AKT pathway.
    Keywords:  Endoplasmic reticulum stressed; Exosomes; Macrophages; PI3K/Akt; Prostate cancer cells
    DOI:  https://doi.org/10.7150/jca.81933
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