bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022‒09‒25
nine papers selected by
Susan Logue
University of Manitoba

  1. Cancer Cell. 2022 Aug 29. pii: S1535-6108(22)00380-4. [Epub ahead of print]
      Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.
    Keywords:  PERK; immunogenic cell death; tumor immunity; type I IFN; unfolded protein responses
  2. Nat Metab. 2022 Sep;4(9): 1166-1184
      Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or β3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic β3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.
  3. Cells. 2022 Sep 16. pii: 2899. [Epub ahead of print]11(18):
      Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging trait of cancer cells. Maladaptive UPR sustains oncogene-driven reprogramming of proteostasis and metabolism and fosters proinflammatory pathways promoting tissue repair and protumorigenic immune responses. However, when cancer cells are exposed to conditions causing irreparable ER homeostasis, such as those elicited by anticancer therapies, the UPR switches from a survival to a cell death program. This lethal ER stress response can elicit immunogenic cell death (ICD), a form of cell death with proinflammatory traits favoring antitumor immune responses. How UPR-driven pathways transit from a protective to a killing modality with favorable immunogenic and proinflammatory output remains unresolved. Here, we discuss key aspects of the functional dichotomy of UPR in cancer cells and how this signal can be harnessed for therapeutic benefit in the context of ICD, especially from the aspect of inflammation aroused by the UPR.
    Keywords:  ER stress; ICD; UPR; cancer; immunogenic cell death; inflammation
  4. Metabolites. 2022 Aug 27. pii: 803. [Epub ahead of print]12(9):
      Elevated concentrations of non-esterified fatty acid (NEFA) induced by negative energy balance (NEB) during the transition period of dairy cows is known to be toxic for multiple bovine cell types. However, the effect of NEFA in bovine mammary epithelial cells (BMECs) remains unclear. The present study aimed to explore the role and molecular mechanism of NEFA in endoplasmic reticulum (ER) stress and the subsequent apoptosis in BMECs. The results showed that NEFA increased ER stress and activated the three unfolded protein response (UPR) signaling sub-pathways by upregulating the expression of GRP78, HSP70, XBP1, ATF6, phosphor-PERK, and phosphor-IRE1α. We also found that NEFA dose-dependently induced apoptosis in BMECs, as indicated by flow cytometry analysis and increased apoptotic gene expression. RNA-seq analysis revealed that NEFA induced apoptosis in BMECs, probably via the ATF4-CHOP axis. Mechanistically, our data showed that NEFA increased reactive oxygen species (ROS) levels, resulting in the activation of the MAPK signaling pathway. Moreover, quercetin, a well-known antioxidant, was found to alleviate ER stress-mediated apoptosis in NEFA-treated BMECs. Collectively, our results suggest that NEFA induces ER stress-mediated apoptosis, probably via the ROS/MAPK signaling pathway, as quercetin has been shown to alleviate ER stress-mediated apoptosis in NEFA-treated BMECs.
    Keywords:  ER stress; apoptosis; bovine mammary epithelial cells; non-esterified fatty acids
  5. Diabet Med. 2022 Sep 24. e14962
      Beta cell ER stress can cause cellular death and dysfunction and has been implicated in the pathogenesis of diabetes. Animal models of beta cell ER stress are critical in further understanding this and for testing novel diabetes therapeutics. The KINGS mouse is model of beta cell ER stress driven by a heterozygous mutation in Ins2. In this study, we investigated how beta cell ER stress in the KINGS mouse drives diabetes. We found that whilst the unfolded protein response (UPR) was upregulated in KINGS islets with increased protein expression of markers of all three UPR arms, this was not associated with a mass loss of beta cells; beta cell apoptosis rates did not increase until after the development of overt diabetes and beta cell mass was maintained. We therefore propose that the KINGS mouse represents a model where beta cell maladaptive UPR signalling drives diabetes development without causing mass beta cell loss.
    Keywords:  apoptosis; beta cell; beta cell mass; endoplasmic reticulum stress; unfolded protein response
  6. Viruses. 2022 Sep 02. pii: 1948. [Epub ahead of print]14(9):
      Viral coinfections can modulate the severity of parasitic diseases, such as human cutaneous leishmaniasis. Leishmania parasites infect thousands of people worldwide and cause from single cutaneous self-healing lesions to massive mucosal destructive lesions. The transmission to vertebrates requires the bite of Phlebotomine sandflies, which can also transmit Phlebovirus. We have demonstrated that Leishmania infection requires and triggers the Endoplasmic stress (ER stress) response in infected macrophages. In the present paper, we tested the hypothesis that ER stress is increased and required for the aggravation of Leishmania infection due to coinfection with Phlebovirus. We demonstrated that Phlebovirus Icoaraci induces the ER stress program in macrophages mediated by the branches IRE/XBP1 and PERK/ATF4. The coinfection with L. amazonensis potentiates and sustains the ER stress, and the inhibition of IRE1α or PERK results in poor viral replication and decreased parasite load in macrophages. Importantly, we observed an increase in viral replication during the coinfection with Leishmania. Our results demonstrated the role of ER stress branches IRE1/XBP1 and PERK/ATF4 in the synergic effect on the Leishmania increased load during Phlebovirus coinfection and suggests that Leishmania infection can also increase the replication of Phlebovirus in macrophages.
    Keywords:  ER stress; Leishmania; Phlebovirus
  7. Front Mol Biosci. 2022 ;9 928006
      Background: Kidney renal clear cell carcinoma (KIRC) is one of the most lethal malignant tumors with a propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress served as a pivotal role in the progression of the tumor. However, the implications of ER stress on the clinical outcome and immune features of KIRC patients still need elucidation. Methods: We identified differentially expressed ER stress-related genes between KIRC specimens and normal specimens with TCGA dataset. Then, we explored the biological function and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, LASSO analysis and univariate Cox regression analysis were applied to construct a novel prognostic model based on ER stress-related DEGs. Next, we confirmed the predictive performance of this model with the GEO dataset and explored the potential biological functions by functional enrichment analysis. Finally, KIRC patients stratified by the prognostic model were assessed for tumor microenvironment (TME), immune infiltration, and immune checkpoints through single-sample Gene Set Enrichment Analysis (ssGSEA) and ESTIMATE analysis. Results: We constructed a novel prognostic model, including eight ER stress-related DEGs, which could stratify two risk groups in KIRC. The prognostic model and a model-based nomogram could accurately predict the prognosis of KIRC patients. Functional enrichment analysis indicated several biological functions related to the progression of KIRC. The high-risk group showed higher levels of tumor infiltration by immune cells and higher immune scores. Conclusion: In this study, we constructed a novel prognostic model based on eight ER stress-related genes for KIRC patients, which would help predict the prognosis of KIRC and provide a new orientation to further research studies on personalized immunotherapy in KIRC.
    Keywords:  endoplasmic reticulum stress; immunotherapy; kidney renal clear cell carcinoma; prognosis; tumor microenvironment
  8. Front Genet. 2022 ;13 944105
      Background: Gastric adenocarcinoma (GAC) is a common clinical malignancy with a poor prognosis. Endoplasmic reticulum (ER) stress plays important roles in the progression, immune filtration, and chemoresistance of cancers. However, whether ER stress-related gene signatures can predict the prognosis of GAC patients remains unknown. Methods: GAC patient RNA-seq data downloaded from The Cancer Genome Atlas and gastric cancer patient microarray data from Gene Expression Omnibus datasets were analyzed using LASSO regression to construct an ER stress-related signature. Survival analysis, time-dependent receiver operating characteristic (ROC) curves, and Cox regression analysis were used to verify the efficacy of the signature. Immune infiltration, somatic mutation, immune checkpoint, and copy number variation analyses were utilized to explore the potential biological significance of the signature. Results: In the present study, eight ER stress-related gene signatures were constructed. Survival analysis showed that patients in the high-risk group had a significantly worse prognosis. The area under the time-dependent ROC curves was 0.65, 0.70, and 0.63 at 1, 3, and 5 years, respectively, in the training cohort. Cox regression analysis showed that the signature is an independent prognostic factor. To predict GAC patients' prognosis meeting individual needs, a nomogram was constructed with good accuracy. In addition, gene set enrichment and immune infiltration analyses showed that the ER stress-related signature is associated with cancer-related pathway activation and an immunosuppressive tumor microenvironment in GAC. Conclusion: In the current study, we established an ER stress-related signature. This prognostic signature has good predictive power and could facilitate the development of novel strategies for the clinical treatment of GAC.
    Keywords:  endoplasmic reticulum stress; gastric adenocarcinoma; immune checkpoint inhibitors; immune filtration; prognostic signature
  9. Toxicol Appl Pharmacol. 2022 Sep 15. pii: S0041-008X(22)00389-1. [Epub ahead of print] 116244
      Stress contributes to the development of many human diseases, including cancer. Based on the source of stress, it can be divided into external stress, such as environmental carcinogens, chemicals, and radiation, and internal stress, like endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Nuclear Protein 1 (NUPR1, p8 or Com-1) is a small, highly basic transcriptional regulator that participates in regulating a variety of cellular processes including DNA repair, ER stress, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis and chromatin remodeling. A large number of studies have reported that NUPR1 expression can be stimulated rapidly in response to various stresses. Thus, NUPR1 is also known as a stress-response gene. Since the role of NUPR1 in breast cancer was identified in 1999, an increasing number of studies sought to reveal its function in cancer. High expression of NUPR1 has been identified in oral squamous cell carcinoma, breast cancer, lung cancer, multiple myeloma, liver cancer and renal cancer. In this review, we summarize current studies of NUPR1 in response to multiple external stressors and internal stressors, and its role in mediating stressors to cause different cell signaling responses. In addition, this review discusses the function of NUPR1 in carcinogenesis, tumorigenesis, metastasis, and cancer therapy. Thus, this review gives a comprehensive insight into the role of NUPR1 in mediating signals from stress to different cell responses, and this process plays a role in the development of cancer.
    Keywords:  Cancer; Environmental stress; External stress; Internal stress; NUPR1