bims-ershed 2022-07-17 papers

bims-ershed

Biomed News

on ER Stress in Health and Diseases

Issue of 2022‒07‒17
nine papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells.
Discovery of toxoflavin, a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition.
The clinical relevance of unfolded protein response signaling in breast cancer.
Inhibition of IRE1α RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors.
C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration.
The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration.
Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine.
The DDR-related gene signature with cell cycle checkpoint function predicts prognosis, immune activity, and chemoradiotherapy response in lung adenocarcinoma.

Trends Cancer. 2022 Jul 08. pii: S2405-8033(22)00134-0. [Epub ahead of print]

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.

Camilla Salvagno, Jessica K Mandula, Paulo C Rodriguez, Juan R Cubillos-Ruiz.

  The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anticancer immunity. We highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation.

Keywords:  ER stress; cancer therapy; immune cells; tumor microenvironment; unfolded protein response

DOI:  https://doi.org/10.1016/j.trecan.2022.06.006
bioRxiv. 2022 Jun 13. pii: 2021.12.30.474519. [Epub ahead of print]

SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells.

Long C Nguyen, David M Renner, Diane Silva, Dongbo Yang, Nicholas Parenti, Kaeri M Medina, Vlad Nicolaescu, Haley Gula, Nir Drayman, Andrea Valdespino, Adil Mohamed, Christopher Dann, Kristin Wannemo, Lydia Robinson-Mailman, Alan Gonzalez, Letícia Stock, Mengrui Cao, Zeyu Qiao, Raymond E Moellering, Savas Tay, Glenn Randall, Michael F Beers, Marsha Rich Rosner, Scott A Oakes, Susan R Weiss.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.IMPORTANCE: SARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.

DOI: https://doi.org/10.1101/2021.12.30.474519
Acta Pharmacol Sin. 2022 Jul 15.

Discovery of toxoflavin, a potent IRE1α inhibitor acting through structure-dependent oxidative inhibition.

Kai-Long Jiang, Chang-Mei Liu, Li-Tong Nie, Hai-Ni Jiang, Lei Xu, Kun-Zhi Zhang, Li-Xia Fan, An-Hui Gao, Lu-Ling Lin, Xiang-Yu Wang, Ming-Jia Tan, Qi-Qing Zhang, Yu-Bo Zhou, Jia Li.

  Inositol-requiring enzyme 1α (IRE1α) is the most conserved endoplasmic reticulum (ER) stress sensor with two catalytic domains, kinase and RNase, in its cytosolic portion. IRE1α inhibitors have been used to improve existing clinical treatments against various cancers. In this study we identified toxoflavin (TXF) as a new-type potent small molecule IRE1α inhibitor. We used luciferase reporter systems to screen compounds that inhibited the IRE1α-XBP1s signaling pathway. As a result, TXF was found to be the most potent IRE1α RNase inhibitor with an IC50 value of 0.226 μM. Its inhibitory potencies on IRE1α kinase and RNase were confirmed in a series of cellular and in vitro biochemical assays. Kinetic analysis showed that TXF caused time- and reducing reagent-dependent irreversible inhibition on IRE1α, implying that ROS might participate in the inhibition process. ROS scavengers decreased the inhibition of IRE1α by TXF, confirming that ROS mediated the inhibition process. Mass spectrometry analysis revealed that the thiol groups of four conserved cysteine residues (CYS-605, CYS-630, CYS-715 and CYS-951) in IRE1α were oxidized to sulfonic groups by ROS. In molecular docking experiments we affirmed the binding of TXF with IRE1α, and predicted its binding site, suggesting that the structure of TXF itself participates in the inhibition of IRE1α. Interestingly, CYS-951 was just near the docked site. In addition, the RNase IC50 and ROS production in vitro induced by TXF and its derivatives were negative correlated (r = -0.872). In conclusion, this study discovers a new type of IRE1α inhibitor that targets a predicted new alternative site located in the junction between RNase domain and kinase domain, and oxidizes conserved cysteine residues of IRE1α active sites to inhibit IRE1α. TXF could be used as a small molecule tool to study IRE1α's role in ER stress.

Keywords:  IRE1α; XBP1; endoplasmic reticulum stress; reactive oxygen species; toxoflavin

DOI:  https://doi.org/10.1038/s41401-022-00949-9
Am J Cancer Res. 2022 ;12(6): 2627-2640

The clinical relevance of unfolded protein response signaling in breast cancer.

Masanori Oshi, Arya Mariam Roy, Shipra Gandhi, Yoshihisa Tokumaru, Li Yan, Akimitsu Yamada, Itaru Endo, Kazuaki Takabe.

Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.

Keywords: Biomarker; breast cancer; gene expression; hormonal; unfolded protein response
J Cell Mol Med. 2022 Jul 13.

Inhibition of IRE1α RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors.

Stuart Creedican, Claire M Robinson, Katarzyna Mnich, Md Nahidul Islam, Eva Szegezdi, Ruth Clifford, Janusz Krawczyk, John B Patterson, Stephen P FitzGerald, Mark Summers, Ciaran Richardson, Kenneth Martin, Adrienne M Gorman, Afshin Samali.

DOI: https://doi.org/10.1111/jcmm.17479
Front Aging. 2022 ;3 916118

C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration.

Francisco José Naranjo-Galindo, Ruixue Ai, Evandro Fei Fang, Hilde Loge Nilsen, Tanima SenGupta.

  Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Caenorhabditis elegans; DNA repair; Parkinson’s disease; aging; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fragi.2022.916118
Front Cell Neurosci. 2022 ;16 836885

The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration.

Anna Konopka, Julie D Atkin.

  Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided evidence that DNA damage and its subsequent repair are important processes in the physiology and normal function of neurons. Neurons are unique cells that form new neural connections throughout life by growth and re-organisation in response to various stimuli. This "plasticity" is essential for cognitive processes such as learning and memory as well as brain development, sensorial training, and recovery from brain lesions. Interestingly, recent evidence has suggested that the formation of double strand breaks (DSBs) in DNA, the most toxic form of damage, is a physiological process that modifies gene expression during normal brain activity. Together with subsequent DNA repair, this is thought to underlie neural plasticity and thus control neuronal function. Interestingly, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease, manifest by a decline in cognitive functions, which are governed by plasticity. This suggests that DNA damage and DNA repair processes that normally function in neural plasticity may contribute to neurodegeneration. In this review, we summarize current understanding about the relationship between DNA damage and neural plasticity in physiological conditions, as well as in the pathophysiology of neurodegenerative diseases.

Keywords:  DNA damage; DNA repair; neural plasticity; neurodegeneration; synaptic plasticity

DOI:  https://doi.org/10.3389/fncel.2022.836885
Nucleic Acids Res. 2022 Jul 12. pii: gkac545. [Epub ahead of print]

Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine.

Aldo Spanjaard, Ronak Shah, Daniël de Groot, Olimpia Alessandra Buoninfante, Ben Morris, Cor Lieftink, Colin Pritchard, Lisa M Zürcher, Shirley Ormel, Joyce J I Catsman, Renske de Korte-Grimmerink, Bjørn Siteur, Natalie Proost, Terry Boadum, Marieke van de Ven, Ji-Ying Song, Maaike Kreft, Paul C M van den Berk, Roderick L Beijersbergen, Heinz Jacobs.

Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.

DOI: https://doi.org/10.1093/nar/gkac545
Respir Res. 2022 Jul 15. 23(1): 190

The DDR-related gene signature with cell cycle checkpoint function predicts prognosis, immune activity, and chemoradiotherapy response in lung adenocarcinoma.

Quan Li, Pan Zhang, Huixiao Hu, Hang Huang, Dong Pan, Guangyun Mao, Burong Hu.

  BACKGROUND: As a DNA surveillance mechanism, cell cycle checkpoint has recently been discovered to be closely associated with lung adenocarcinoma (LUAD) prognosis. It is also an essential link in the process of DNA damage repair (DDR) that confers resistance to radiotherapy. Whether genes that have both functions play a more crucial role in LUAD prognosis remains unclear.METHODS: In this study, DDR-related genes with cell cycle checkpoint function (DCGs) were selected to investigate their effects on the prognosis of LUAD. The TCGA-LUAD cohort and two GEO external validation cohorts (GSE31210 and GSE42171) were performed to construct a prognosis model based on the least absolute shrinkage and selection operator (LASSO) regression. Patients were divided into high-risk and low-risk groups based on the model. Subsequently, the multivariate COX regression was used to construct a prognostic nomogram. The ssGSEA, CIBERSORT algorithm, TIMER tool, CMap database, and IC50 of chemotherapeutic agents were used to analyze immune activity and responsiveness to chemoradiotherapy.
RESULTS: 4 DCGs were selected as prognostic signatures, and patients in the high-risk group had a lower overall survival (OS). The lower infiltration levels of immune cells and the higher expression levels of immune checkpoints appeared in the high-risk group. The damage repair pathways were upregulated, and chemotherapeutic agent sensitivity was poor in the high-risk group.
CONCLUSIONS: The 4-DCGs signature prognosis model we constructed could predict the survival rate, immune activity, and chemoradiotherapy responsiveness of LUAD patients.

Keywords:  Cancer prognosis; Cell cycle checkpoint; DNA damage repair; Gene signature; Lung adenocarcinoma

DOI:  https://doi.org/10.1186/s12931-022-02110-w