bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024‒02‒04
six papers selected by
Susan Logue, University of Manitoba
  1. Regulation of cardiac fibroblast cell death by unfolded protein response signaling.
  2. Tumorous IRE1α facilitates CD8+T cells-dependent anti-tumor immunity and improves immunotherapy efficacy in melanoma.
  3. Emerging mechanisms of the unfolded protein response in therapeutic resistance: from chemotherapy to Immunotherapy.
  4. The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.
  5. "Sticki-ER": functions of the platelet endoplasmic reticulum.
  6. Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells.
  1. Front Physiol. 2023 ;14 1304669
    Regulation of cardiac fibroblast cell death by unfolded protein response signaling.
    Mary B Rowland, Patrick E Moore, Robert N Correll.
      The endoplasmic reticulum (ER) is a tightly regulated organelle that requires specific environmental properties to efficiently carry out its function as a major site of protein synthesis and folding. Embedded in the ER membrane, ER stress sensors inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) serve as a sensitive quality control system collectively known as the unfolded protein response (UPR). In response to an accumulation of misfolded proteins, the UPR signals for protective mechanisms to cope with the cellular stress. Under prolonged unstable conditions and an inability to regain homeostasis, the UPR can shift from its original adaptive response to mechanisms leading to UPR-induced apoptosis. These UPR signaling pathways have been implicated as an important feature in the development of cardiac fibrosis, but identifying effective treatments has been difficult. Therefore, the apoptotic mechanisms of UPR signaling in cardiac fibroblasts (CFs) are important to our understanding of chronic fibrosis in the heart. Here, we summarize the maladaptive side of the UPR, activated downstream pathways associated with cell death, and agents that have been used to modify UPR-induced apoptosis in CFs.
    Keywords:  apoptosis; cardiac fibroblast; cell death; er stress; fibrosis; unfolded protein response
    DOI:  https://doi.org/10.3389/fphys.2023.1304669
  2. Cell Commun Signal. 2024 Jan 30. 22(1): 83
    Tumorous IRE1α facilitates CD8+T cells-dependent anti-tumor immunity and improves immunotherapy efficacy in melanoma.
    Yuqi Yang, Sijia Wang, Xiang-Xu Wang, Sen Guo, Huina Wang, Qiong Shi, Yangzi Tian, Hao Wang, Tao Zhao, Hengxiang Zhang, Baolu Zhang, Tianwen Gao, Chunying Li, Xiuli Yi, Weinan Guo.
      BACKGROUND: Tumor cells frequently suffer from endoplasmic reticulum (ER) stress. Previous studies have extensively elucidated the role of tumorous unfolded protein response in melanoma cells, whereas the effect on tumor immunology and the underlying mechanism remain elusive.METHODS: Bioinformatics, biochemical assays and pre-clinical mice model were employed to demonstrate the role of tumorous inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in anti-tumor immunity and the underlying mechanism.
    RESULTS: We firstly found that IRE1α signaling activation was positively associated with the feature of tumor-infiltrating lymphocytes. Then, pharmacological ER stress induction by HA15 exerted prominent anti-tumor effect in immunocompetent mice and was highly dependent on CD8+T cells, paralleled with the reshape of immune cells in tumor microenvironment via tumorous IRE1α-XBP1 signal. Subsequently, tumorous IRE1α facilitated the expression and secretion of multiple chemokines and cytokines via XBP1-NF-κB axis, leading to increased infiltration and anti-tumor capacity of CD8+T cells. Ultimately, pharmacological induction of tumorous ER stress by HA15 brought potentiated therapeutic effect along with anti-PD-1 antibody on melanoma in vivo.
    CONCLUSIONS: Tumorous IRE1α facilitates CD8+T cells-dependent anti-tumor immunity and improves immunotherapy efficacy by regulating chemokines and cytokines via XBP1-NF-κB axis. The combination of ER stress inducer and anti-PD-1 antibody could be promising for increasing the efficacy of melanoma immunotherapy.
    Keywords:  Anti-PD-1 antibody; ER stress; Immunosurveillance; Immunotherapy; Melanoma
    DOI:  https://doi.org/10.1186/s12964-024-01470-8
  3. Cell Commun Signal. 2024 Jan 31. 22(1): 89
    Emerging mechanisms of the unfolded protein response in therapeutic resistance: from chemotherapy to Immunotherapy.
    Jiang He, You Zhou, Lunquan Sun.
      The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR). As an adaptive cellular response to hostile microenvironments, such as hypoxia, nutrient deprivation, oxidative stress, and chemotherapeutic drugs, the UPR is activated in diverse cancer types and functions as a dynamic tumour promoter in cancer development; this role of the UPR indicates that regulation of the UPR can be utilized as a target for tumour treatment. T-cell exhaustion mainly refers to effector T cells losing their effector functions and expressing inhibitory receptors, leading to tumour immune evasion and the loss of tumour control. Emerging evidence suggests that the UPR plays a crucial role in T-cell exhaustion, immune evasion, and resistance to immunotherapy. In this review, we summarize the molecular basis of UPR activation, the effect of the UPR on immune evasion, the emerging mechanisms of the UPR in chemotherapy and immunotherapy resistance, and agents that target the UPR for tumour therapeutics. An understanding of the role of the UPR in immune evasion and therapeutic resistance will be helpful to identify new therapeutic modalities for cancer treatment. Video Abstract.
    Keywords:  Chemotherapy; Immune checkpoint therapy; T-cell exhaustion; Unfolded protein response
    DOI:  https://doi.org/10.1186/s12964-023-01438-0
  4. Cancer Lett. 2024 Jan 28. pii: S0304-3835(24)00064-8. [Epub ahead of print] 216671
    The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.
    Gilles Riegel, Christophe Orvain, Sevda Recberlik, Marie-Elodie Spaety, Gernot Poschet, Aina Venkatasamy, Masami Yamamoto, Sachiyo Nomura, Tetsyua Tsukamoto, Murielle Masson, Isabelle Gross, Ronan Le Lagadec, Georg Mellitzer, Christian Gaiddon.
      Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.
    Keywords:  Caspase-independent apoptosis; ER stress; Glutathione; Metabolism; RDC11; Transsulfuration; UPR
    DOI:  https://doi.org/10.1016/j.canlet.2024.216671
  5. Antioxid Redox Signal. 2024 Jan 29.
    "Sticki-ER": functions of the platelet endoplasmic reticulum.
    Yvonne Kong, Joyce Chiu, Freda H Passam.
      SIGNIFICANCE: Platelets are the smallest cells in circulation (measuring 2 microns in diameter). Platelet activation is necessary for thrombus formation and relies on calcium mobilisation from the endoplasmic reticulum (ER). Platelet activation leads to mobilization of ER resident proteins to the platelet surface; these are essential for the function of platelet receptors and intercellular interactions.RECENT ADVANCES: ER homeostasis is maintained by an appropriate redox balance, regulated calcium stores and normal protein folding. Disruption of platelet ER homeostasis can cause ER stress which contributes to platelet activation. ER stress results in the externalisation of ER proteins to the cell surface, including members of the protein disulfide isomerase family and chaperones.
    CRITICAL ISSUES: The ER is central to platelet function, but our understanding of its regulation is incomplete. Previous studies have focused on the function of platelet protein disulfide isomerase family members in the extracellular space, and much less on their intracellular role. How platelets maintain ER homeostasis and how they direct ER chaperone proteins to facilitate intercellular signalling is unknown.
    FUTURE DIRECTIONS: An understanding of ER functions in the platelet is essential as these may determine critical platelet activities such as secretion and adhesion. Studies are necessary to understand the redox reactions of platelet disulfide isomerases in the intracellular versus extracellular space, as these differentially affect platelet function. Unresolved questions are how platelet ER proteins control calcium release and protein folding in response to ER stress. Targeting the platelet ER may have therapeutic application in metabolic and neoplastic disease.
    DOI:  https://doi.org/10.1089/ars.2024.0566
  6. BMC Biol. 2024 Jan 30. 22(1): 23
    Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells.
    Seon Yong Lee, Sang-Hun Choi, Yoonji Kim, Hee-Sung Ahn, Young-Gyu Ko, Kyunggon Kim, Sung Wook Chi, Hyunggee Kim.
      BACKGROUND: Glioblastoma (GBM) is more difficult to treat than other intractable adult tumors. The main reason that GBM is so difficult to treat is that it is highly infiltrative. Migrasomes are newly discovered membrane structures observed in migrating cells. Thus, they can be generated from GBM cells that have the ability to migrate along the brain parenchyma. However, the function of migrasomes has not yet been elucidated in GBM cells.RESULTS: Here, we describe the composition and function of migrasomes generated along with GBM cell migration. Proteomic analysis revealed that LC3B-positive autophagosomes were abundant in the migrasomes of GBM cells. An increased number of migrasomes was observed following treatment with chloroquine (CQ) or inhibition of the expression of STX17 and SNAP29, which are involved in autophagosome/lysosome fusion. Furthermore, depletion of ITGA5 or TSPAN4 did not relieve endoplasmic reticulum (ER) stress in cells, resulting in cell death.
    CONCLUSIONS: Taken together, our study suggests that increasing the number of autophagosomes, through inhibition of autophagosome/lysosome fusion, generates migrasomes that have the capacity to alleviate cellular stress.
    Keywords:  Autophagosome; Cell death; ER stress; ITGA5; Migrasome; Retraction fiber; TSPAN4
    DOI:  https://doi.org/10.1186/s12915-024-01829-w
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