bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒09‒12
thirteen papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. Nat Commun. 2021 Sep 07. 12(1): 5321
      CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.
  2. Reprod Toxicol. 2021 Sep 04. pii: S0890-6238(21)00138-6. [Epub ahead of print]105 120-127
      Maternal cigarette smoking (CS) and pre-eclampsia (PE) alter placental function and expression of important proteins which maintain homeostasis. Two interlinked pathways of interest are the unfolded protein response (UPR) and apoptosis. The UPR is upregulated in the PE placenta, but no data is available on the effects of CS and how it correlates with apoptotic expression. Samples of human placental tissue from normotensive non-smokers (n = 8), women with PE (n = 8), and CS (n = 8) were analysed using immunohistochemistry for 3 UPR markers (phosphorylated PKR-like endoplasmic reticulum (ER) kinase (pPERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6)), and an antibody microarray for 19 apoptotic and stress regulating markers. For the PE group compared to the normotensive group, staining for pPERK was increased in decidual tissue and villi, and for IRE1, the overall percentage of stained villi per field of view was increased. There were no differences in UPR expression comparing CS to controls. Of the apoptotic markers, only IκBα (Ser32/36), which is part of an inhibitory pathway, showed a significant decrease in the PE and CS groups compared to controls. These findings suggest UPR regulation is more evident in PE with a general increase in ER stress due to decreased inhibition of apoptosis as compared to CS for which UPR was not altered.
    Keywords:  Cell death; Nicotine; PERK; Pre-eclampsia; Protein folding; UPR
  3. Curr Opin Plant Biol. 2021 Sep 03. pii: S1369-5266(21)00106-0. [Epub ahead of print]63 102106
      Maintaining the integrity of organelles despite the cellular disturbances that arise during stress is essential for life. To ensure organelle proteostasis (protein homeostasis), plants have evolved multitiered quality control mechanisms that work together to repair or recycle the damaged organelles. Despite recent advances, our understanding of plant organelle quality control mechanisms is far from complete. Especially, the crosstalk between different quality control pathways remains elusive. Here, we highlight recent advances on organelle quality control, focusing on the targeted protein degradation pathways that maintain the homeostasis of the endoplasmic reticulum (ER), chloroplast, and mitochondria. We discuss how plant cells decide to employ different degradation pathways and propose tools that could be used to discover the missing components in organelle quality control.
    Keywords:  CDC48; Model substrates; Organelle quality control; Proteasome; Selective autophagy; Unfolded protein response; Viral replication
  4. Cell Stress Chaperones. 2021 Sep 08.
      Human periodontal ligament fibroblast (HPDLF) is a major component of the resident cells in the periodontal microenvironment, and plays important roles in periodontitis through multiple mechanisms. Although lipopolysaccharide (LPS) has been shown to cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) in HPDLF, the mechanisms governing HPDLF function in periodontitis are unclear. In this study, we tested the ability of unfolded protein response (UPR) to regulate HPDLF in vitro and examined the underlying mechanisms. We found LPS-pretreated HPDLF induced macrophage polarization toward M1 phenotype. UPR activation reduced the inflammatory cytokine production and downregulated the expression of TLR4 in HPDLF. The phosphorylation of NF-κB p65 and I-κB was also inhibited by UPR activation. Our findings demonstrate that the connection of LPS, UPR, and HPDLF may represent a new concrete theory of innate immunity regulation in periodontal diseases, and suggest that targeting of UPR in HPDLF may be developed as a potent therapy for periodontitis.
    Keywords:  HPDLF; LPS; Macrophage; Periodontitis; UPR
  5. Am J Chin Med. 2021 Sep 06. 1-16
      Type 1 diabetes (T1D) is an autoimmune and inflammatory disease with excessive loss of pancreatic islet [Formula: see text]-cells. Accumulating evidence indicated that endoplasmic reticulum (ER) stress played a critical role in [Formula: see text]-cells loss, leading to T1D. Therefore, promoting the survival of pancreatic [Formula: see text]cells would be beneficial for patients with T1D. Puerarin is a natural isoflavone that has been demonstrated to be able to decrease blood glucose in patients with T1D. However, it remains unknown whether puerarin improves ER stress to prevent [Formula: see text]-cells from apoptosis. Here, we sought to investigate the role of puerarin in ER stress-associated apoptosis and explore its underlying mechanism in the mouse insulinoma cell line (MIN6). Flow cytometry and cell counting kit-8 (CCK8) experiments showed that puerarin caused a significant increase in the viability of MIN6 cells injured by H2O2. Furthermore, the protein kinase R-like ER kinase (PERK) signal pathway, a critical branch of ER stress response, was found to be involved in this process. Puerarin inhibited the phosphorylation of PERK, subsequently suppressed the phosphorylation of eukaryotic initiation factor 2[Formula: see text] (eIF2[Formula: see text], then decreased the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, ultimately attenuating ER stress to prevent MIN6 cells from apoptosis. In addition, puerarin inhibited the activation of Janus kinase 2 (JAK2)/signal transducer and activators of transcription 3 (STAT3), which suppressed the PERK signal cascade with decreased ATF4 and CHOP levels. Taken together, our results firstly demonstrated that puerarin could prevent MIN6 cells from apoptosis at least in part by inhibiting the PERK-eIF2[Formula: see text]-ATF4-CHOP axis under ER stress conditions, which might be mediated by inactivation of the JAK2/STAT3 signal pathway. Therefore, investigating the mechanism underlying the effects of puerarin might highlight the potential roles of puerarin developing into an antidiabetic drug.
    Keywords:  ER Stress; JAK2/STAT3; PERK; Puerarin; Type 1 Diabetes
  6. J Biol Chem. 2021 Sep 02. pii: S0021-9258(21)00965-0. [Epub ahead of print] 101163
      Inactivation of p53 is present in almost every tumor and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53 negative regulators such as MDM2, which mediate the degradation of wild-type (WT) p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) cell line models, we show that two alternatively-spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and which lack the C-terminal MDM2 binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ, and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2 overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups which comprise approximately 6% of all cancers.
    Keywords:  MDM2; RNA degradation; alternative splicing; cancer therapy; mRNA decay; p53; p53β/γ restoration; targeting NMD
  7. Cancers (Basel). 2021 Sep 03. pii: 4443. [Epub ahead of print]13(17):
      Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.
    Keywords:  GSVA; hepatocellular cancer; unfolded protein; unfolded protein score
  8. Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00060-5. [Epub ahead of print]364 195-240
      Transcription is an essential cellular process but also a major threat to genome integrity. Transcription-associated DNA breaks are particularly detrimental as their defective repair can induce gene mutations and oncogenic chromosomal translocations, which are hallmarks of cancer. The past few years have revealed that transcriptional breaks mainly originate from DNA topological problems generated by the transcribing RNA polymerases. Defective removal of transcription-induced DNA torsional stress impacts on transcription itself and promotes secondary DNA structures, such as R-loops, which can induce DNA breaks and genome instability. Paradoxically, as they relax DNA during transcription, topoisomerase enzymes introduce DNA breaks that can also endanger genome integrity. Stabilization of topoisomerases on chromatin by various anticancer drugs or by DNA alterations, can interfere with transcription machinery and cause permanent DNA breaks and R-loops. Here, we review the role of transcription in mediating DNA breaks, and discuss how deregulation of topoisomerase activity can impact on transcription and DNA break formation, and its connection with cancer.
    Keywords:  Cancer; DNA break; DNA topology; Genome instability; Oncogenic translocation; R-loop; RNA polymerase; RNA/DNA hybrid; Topoisomerase; Transcription
  9. RNA. 2021 Sep 08. pii: rna.078880.121. [Epub ahead of print]
      The expression of bromodomain-containing proteins that regulate chromatin structure and accessibility must be tightly controlled to ensure the appropriate regulation of gene expression. In the yeast S. cerevisiae, Bromodomain Factor 2 (BDF2) expression is extensively regulated post-transcriptionally during stress by RNase III-mediated decay (RMD), which is triggered by cleavage of the BDF2 mRNA in the nucleus by the RNase III homologue Rnt1p. Previous studies have shown that RMD-mediated down-regulation of BDF2 is hyper-activated in osmotic stress conditions, yet the mechanisms driving the enhanced nuclear cleavage of BDF2 RNA under these conditions remain unknown. Here, we show that RMD hyper-activation can be detected in multiple stress conditions that inhibit mRNA export, and that Rnt1p remains primarily localized in the nucleus during salt stress. We show that globally inhibiting mRNA nuclear export by anchoring away mRNA biogenesis or export factors out of the nucleus can recapitulate RMD hyper-activation in the absence of stress. RMD hyperactivation requires Rnt1p nuclear localization but does not depend on the BDF2 gene endogenous promoter, and its efficiency is affected by the structure of the stem-loop cleaved by Rnt1p. Because multiple stress conditions have been shown to mediate global inhibition of mRNA export, our results suggest that the hyperactivation of RMD is primarily the result of the increased nuclear retention of the BDF2 mRNA during stress.
    Keywords:  Bromodomain; RNase III; Rnt1p; Stress; mRNA export
  10. Int J Mol Sci. 2021 Sep 06. pii: 9649. [Epub ahead of print]22(17):
      The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases-including metabolic organs (intestine and fat body), neurons, and muscles-we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila.
    Keywords:  Drosophila; JNK; aging; lifespan
  11. Int J Mol Sci. 2021 Sep 03. pii: 9558. [Epub ahead of print]22(17):
      Due to their sessile lifestyle, plants are especially exposed to various stresses, including genotoxic stress, which results in altered genome integrity. Upon the detection of DNA damage, distinct cellular responses lead to cell cycle arrest and the induction of DNA repair mechanisms. Interestingly, it has been shown that some cell cycle regulators are not only required for meristem activity and plant development but are also key to cope with the occurrence of DNA lesions. In this review, we first summarize some important regulatory steps of the plant cell cycle and present a brief overview of the DNA damage response (DDR) mechanisms. Then, the role played by some cell cycle regulators at the interface between the cell cycle and DNA damage responses is discussed more specifically.
    Keywords:  DNA damage response; plant cell cycle
  12. Nat Rev Mol Cell Biol. 2021 Sep 10.
      Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.
  13. STAR Protoc. 2021 Sep 17. 2(3): 100668
      Glycosylation is one of the most common protein modifications in living organisms and has important regulatory roles in animal tissue development and homeostasis. Here, we present a protocol for generation of 3D organotypic skin models using CRISPR-Cas9 genetically engineered human keratinocytes (N/TERT-1) to study the role of glycans in epithelial tissue formation. This strategy is also applicable to other gene targets and organotypic tissue models. Careful handling of the cell cultures is critical for the successful formation of the organoids. For complete details on the use and execution of this protocol, please refer to Dabelsteen et al. (2020).
    Keywords:  CRISPR; Cell Biology; Organoids