bims-unfpre 2023-12-24 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–12–24
twelve papers selected by
Susan Logue, University of Manitoba

Unlocking the plant ER stress code: IRE1-proteasome signaling cohort takes the lead.
Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer.
Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts.
A risk signature based on endoplasmic reticulum stress-associated genes predicts prognosis and immunity in pancreatic cancer.
BCL-2 Modulates IRE1α Activation to Attenuate ER Stress and Pulmonary Fibrosis.
Mechanisms of Endoplasmic Reticulum Protein Homeostasis in Plants.
Cellular stress responses as modulators of drug cytotoxicity in pharmacotherapy of glioblastoma.
Adipose-Derived Mesenchymal Stem Cells Protect Endothelial Cells from Hypoxic Injury by Suppressing Terminal UPR In Vivo and In Vitro.
Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice.
Immunogenic Extracellular Vesicles Derived from Endoplasmic Reticulum-Stressed Tumor Cells: Implications as the Therapeutic Cancer Vaccine.
Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways.

Trends Plant Sci. 2023 Dec 14. pii: S1360-1385(23)00388-6. [Epub ahead of print]

Unlocking the plant ER stress code: IRE1-proteasome signaling cohort takes the lead.

Vishal Varshney, Jawahar Singh, Vishnu Mishra.

  In the intricate landscape of cellular function, proper protein folding is pivotal for cellular processes, particularly within the endoplasmic reticulum (ER). In a recent study, Ko et al. reveal a signaling role for inositol-requiring enzyme 1 (IRE1) in ER stress and identify PHOSPHATASE TYPE 2CA (PP2CA)-INTERACTING RING FINGER PROTEIN 1 (PIR1) as a crucial plant-specific regulator, balancing the unfolded protein response (UPR) and ubiquitin-proteasome system (UPS) by modulating ABI5 stability, unveiling intricate stress response connections.

Keywords:  ABI5; E3 ligase; ER stress; PIR1; ubiquitin-proteasome system; unfolded protein response

DOI:  https://doi.org/10.1016/j.tplants.2023.12.003
Drug Res (Stuttg). 2023 Dec 22.

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer.

Alireza Poustforoosh, Sanaz Faramarz, Mohammad Hadi Nematollahi, Mehdi Mahmoodi, Mahdiyeh Azadpour.

BACKGROUND: Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a key role in cancer progression. The aggregation of incorrectly folded proteins in the ER generates ER stress, which in turn activates the UPR as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1 (IRE1) is the most evolutionary conserved ER stress sensor, which plays a pro-tumoral role in various cancers. Targeting its' active sites is one of the most practical approaches for the treatment of cancers.
OBJECTIVE: In this study, we aimed to use the structure of 4μ8C as a template to produce newly designed compounds as IRE1 inhibitors.
METHODS: Various functional groups were added to the 4μ8C, and their binding affinity to the target sites was assessed by conducting a covalent molecular docking study. The potential of the designed compound for further in vitro and in vivo studies was evaluated using ADMET analysis.
RESULTS: Based on the obtained results, the addition of hydroxyl groups to 4μ8C enhanced the binding affinity of the designed compound to the target efficiently. Compound 17, which was constructed by the addition of one hydroxyl group to the structure of 4μ8C, can construct a strong covalent bond with Lys907. The outcomes of ADMET analysis indicated that compound 17 could be considered a drug-like molecule.
CONCLUSION: Our results revealed that designed compound 17 could inhibit IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of IRE1 and introduces a promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1055/a-2211-2218
Antioxidants (Basel). 2023 Nov 21. pii: 2024. [Epub ahead of print]12(12):

Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts.

Jun-Hui Zhan, Juan Wei, Lin Liu, Yi-Tong Xu, Hui Ji, Chang-Nan Wang, Yu-Jian Liu, Xiao-Yan Zhu.

  Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung.

Keywords:  ER stress; ROS; TSP-1; fibroblast; pulmonary fibrosis

DOI:  https://doi.org/10.3390/antiox12122024
Front Mol Biosci. 2023 ;10 1298077

A risk signature based on endoplasmic reticulum stress-associated genes predicts prognosis and immunity in pancreatic cancer.

Haofei Chen, Ning Xu, Jia Xu, Cheng Zhang, Xin Li, Hao Xu, Weixiong Zhu, Jinze Li, Daoming Liang, Wence Zhou.

  Introduction: The involvement of endoplasmic reticulum (ER) stress in cancer biology is increasingly recognized, yet its role in pancreatic cancer (PC) remains unclear. This study aims to elucidate the impact of ER stress on prognosis and biological characteristics in PC patients. Methods: A bioinformatic analysis was conducted using RNA-seq data and clinicopathological information from PC patients in the TCGA and ICGC databases. The ER stress-associated gene sets were extracted from MSigDB. ER stress-associated genes closely linked with overall survival (OS) of PC patients were identified via log-rank test and univariate Cox analysis, and further narrowed by LASSO method. A risk signature associated with ER stress was formulated using multivariate Cox regression and assessed through Kaplan-Meier curves, receiver operating characteristic (ROC) analyses, and Harrell's concordance index. External validation was performed with the ICGC cohort. The single-sample gene-set enrichment analysis (ssGSEA) algorithm appraised the immune cell infiltration landscape. Results: Worse OS in PC patients with high-risk signature score was observed. Multivariate analysis underscored our ER stress-associated signature as a valuable and independent predictor of prognosis. Importantly, these results based on TCGA were further validated in ICGC dataset. In addition, our risk signature was closely associated with homeostasis, protein secretion, and immune regulation in PC patients. In particular, PC microenvironment in the high-risk cluster exhibited a more immunosuppressive status. At last, we established a nomogram model by incorporating the risk signature and clinicopathological parameters, which behaves better in predicting prognosis of PC patients. Discussion: This comprehensive molecular analysis presents a new predictive model for the prognosis of PC patients, highlighting ER stress as a potential therapeutic target. Besides, the findings indicate that ER stress can have effect modulating PC immune responses.

Keywords:  ER stress; bioinformatics; immune microenvironment; pancreatic cancer; prognosis

DOI:  https://doi.org/10.3389/fmolb.2023.1298077
Am J Respir Cell Mol Biol. 2023 Dec 20.

BCL-2 Modulates IRE1α Activation to Attenuate ER Stress and Pulmonary Fibrosis.

Claude Jourdan Le Saux, Tsung Che Ho, Alexis M Brumwell, Jaymin J Kathiriya, Ying Wei, Jun-Wei B Hughes, Kiana Garakani, Kamran Atabai, Vincent C Auyeung, Feroz R Papa, Harold A Chapman.

  BCL-2 family members are known to be pro-survival agents in numerous biological settings. Here we provide evidence that in injury and repair processes in lungs, BCL-2 mainly acts to attenuate endoplasmic reticulum (ER) stress and limit extracellular matrix (ECM) accumulation. Days after intratracheal bleomycin mice lose a fraction of their alveolar type II epithelium from terminal ER stress driven by activation of the critical ER sensor and stress effector IRE1-α. This fraction is dramatically increased by BCL-2 inhibition because IRE1-α activation is dependent on its physical association with the BCL-2-pro-apoptotic family member BAX and we found BCL-2 to disrupt this association in vitro. In vivo, Navitoclax (a BCL-2/BCL-xL inhibitor) given 15-21 days after bleomycin challenge evoked strong activation of IRE-1α in mesenchymal cells and markers of ER stress but not apoptosis. Remarkably, following BCL-2 inhibition, bleomycin-exposed mice demonstrated persistent collagen accumulation at day 42 compared to resolution in controls. Enhanced fibrosis proved to be due to the RNAase activity of IRE1a downregulating MRC2 mRNA and protein, a mediator of collagen turnover. The critical role of MRC2 was confirmed in PCLS cultures of day 42 lungs from bleomycin-exposed WT and MRC2 null mice. Soluble and tissue collagens accumulated in PCLS cultures from Navitoclax-treated, bleomycin challenged mice compared to controls, nearly identical to that of challenged but untreated MRC2 nulls. Thus, apart from mitochondrial-based anti-apoptosis, BCL-2 functions to attenuate ER stress responses, fostering tissue homeostasis and injury repair.

Keywords:  Bcl-2; ER stress, fibrosis, apoptosis, fibroblast, alveolar epithelial cells

DOI:  https://doi.org/10.1165/rcmb.2023-0109OC
Int J Mol Sci. 2023 Dec 18. pii: 17599. [Epub ahead of print]24(24):

Mechanisms of Endoplasmic Reticulum Protein Homeostasis in Plants.

Zhihao Duan, Kai Chen, Tao Yang, Ronghui You, Binzhao Chen, Jianming Li, Linchuan Liu.

  Maintenance of proteome integrity is essential for cell function and survival in changing cellular and environmental conditions. The endoplasmic reticulum (ER) is the major site for the synthesis of secretory and membrane proteins. However, the accumulation of unfolded or misfolded proteins can perturb ER protein homeostasis, leading to ER stress and compromising cellular function. Eukaryotic organisms have evolved sophisticated and conserved protein quality control systems to ensure protein folding fidelity via the unfolded protein response (UPR) and to eliminate potentially harmful proteins via ER-associated degradation (ERAD) and ER-phagy. In this review, we summarize recent advances in our understanding of the mechanisms of ER protein homeostasis in plants and discuss the crosstalk between different quality control systems. Finally, we will address unanswered questions in this field.

Keywords:  Arabidopsis thaliana; ER homeostasis; ER-associated degradation (ERAD); ER-phagy; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/ijms242417599
Biochim Biophys Acta Rev Cancer. 2023 Dec 14. pii: S0304-419X(23)00203-2. [Epub ahead of print]1879(1): 189054

Cellular stress responses as modulators of drug cytotoxicity in pharmacotherapy of glioblastoma.

Magdalena Kusaczuk, Elena Tovar Ambel, Monika Naumowicz, Guillermo Velasco.

  Despite the extensive efforts to find effective therapeutic strategies, glioblastoma (GBM) remains a therapeutic challenge with dismal prognosis of survival. Over the last decade the role of stress responses in GBM therapy has gained a great deal of attention, since depending on the duration and intensity of these cellular programs they can be cytoprotective or promote cancer cell death. As such, initiation of the UPR, autophagy or oxidative stress may either impede or facilitate drug-mediated cell killing. In this review, we summarize the mechanisms that regulate ER stress, autophagy, and oxidative stress during GBM development and progression to later discuss the involvement of these stress pathways in the response to different treatments. We also discuss how a precise understanding of the molecular mechanisms regulating stress responses evoked by different pharmacological agents could decisively contribute to the design of novel and more effective combinational treatments against brain malignancies.

Keywords:  Autophagy; ER stress; Glioblastoma; Oxidative stress; Pharmacotherapy

DOI:  https://doi.org/10.1016/j.bbcan.2023.189054
Int J Mol Sci. 2023 Dec 06. pii: 17197. [Epub ahead of print]24(24):

Adipose-Derived Mesenchymal Stem Cells Protect Endothelial Cells from Hypoxic Injury by Suppressing Terminal UPR In Vivo and In Vitro.

Michael Keese, Jiaxing Zheng, Kaixuan Yan, Karen Bieback, Benito A Yard, Prama Pallavi, Christoph Reissfelder, Mark Andreas Kluth, Martin Sigl, Vugar Yugublu.

  Adipose-derived stem cells (ASCs) have been used as a therapeutic intervention for peripheral artery disease (PAD) in clinical trials. To further explore the therapeutic mechanism of these mesenchymal multipotent stromal/stem cells in PAD, this study was designed to test the effect of xenogeneic ASCs extracted from human adipose tissue on hypoxic endothelial cells (ECs) and terminal unfolded protein response (UPR) in vitro and in an atherosclerosis-prone apolipoprotein E-deficient mice (ApoE-/- mice) hindlimb ischemia model in vivo. ASCs were added to Cobalt (II) chloride-treated ECs; then, metabolic activity, cell migration, and tube formation were evaluated. Fluorescence-based sensors were used to assess dynamic changes in Ca2+ levels in the cytosolic- and endoplasmic reticulum (ER) as well as changes in reactive oxygen species. Western blotting was used to observe the UPR pathway. To simulate an acute-on-chronic model of PAD, ApoE-/- mice were subjected to a double ligation of the femoral artery (DLFA). An assessment of functional recovery after DFLA was conducted, as well as histology of gastrocnemius. Hypoxia caused ER stress in ECs, but ASCs reduced it, thereby promoting cell survival. Treatment with ASCs ameliorated the effects of ischemia on muscle tissue in the ApoE-/- mice hindlimb ischemia model. Animals showed less muscle necrosis, less inflammation, and lower levels of muscle enzymes after ASC injection. In vitro and in vivo results revealed that all ER stress sensors (BIP, ATF6, CHOP, and XBP1) were activated. We also observed that the expression of these proteins was reduced in the ASCs treatment group. ASCs effectively alleviated endothelial dysfunction under hypoxic conditions by strengthening ATF6 and initiating a transcriptional program to restore ER homeostasis. In general, our data suggest that ASCs may be a meaningful treatment option for patients with PAD who do not have traditional revascularization options.

Keywords:  adipose-derived stem cells; critical limb ischemia; endoplasmic reticulum; hypoxia; peripheral artery disease; unfolded protein response

DOI:  https://doi.org/10.3390/ijms242417197
Cell Death Dis. 2023 Dec 20. 14(12): 848

Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice.

Atsuhiko Ichimura, Yuu Miyazaki, Hiroki Nagatomo, Takaaki Kawabe, Nobuhisa Nakajima, Ga Eun Kim, Masato Tomizawa, Naoki Okamoto, Shinji Komazaki, Sho Kakizawa, Miyuki Nishi, Hiroshi Takeshima.

TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the endoplasmic reticulum (ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca2+ release in various cell types. Serious mutations in the TRIC-B (also referred to as TMEM38B) locus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported that Tric-b-knockout mice can be used as an OI model; Tric-b deficiency deranges ER Ca2+ handling and thus reduces extracellular matrix (ECM) synthesis in osteoblasts, leading to poor mineralization. Here we report irregular cell death and insufficient ECM in long-bone growth plates from Tric-b-knockout embryos. In the knockout growth plate chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, activated PERK/eIF2α (PKR-like ER kinase/ eukaryotic initiation factor 2α) signaling seemed to inordinately alter gene expression to induce apoptosis-related proteins including CHOP (CCAAT/enhancer binding protein homologous protein) and caspase 12 in the knockout chondrocytes. Ca2+ imaging detected aberrant Ca2+ handling in the knockout chondrocytes; ER Ca2+ release was impaired, while cytoplasmic Ca2+ level was elevated. Our observations suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic states by compromising cellular Ca2+-handling and exacerbating ER stress response, leading to impaired ECM synthesis and accidental cell death.

DOI: https://doi.org/10.1038/s41419-023-06285-y
ACS Nano. 2023 Dec 18.

Immunogenic Extracellular Vesicles Derived from Endoplasmic Reticulum-Stressed Tumor Cells: Implications as the Therapeutic Cancer Vaccine.

Kyung Hee Han, Chan Ho Kim, So Hee Kim, Chang Hyun Lee, Minsung Park, Van Dat Bui, Van Hieu Duong, Seunglee Kwon, Minji Ha, Heegun Kang, Jae Hyung Park.

  Tumor-derived extracellular vesicles (TDEs) have potential for therapeutic cancer vaccine applications since they innately possess tumor-associated antigens, mediate antigen presentation, and can incorporate immune adjuvants for enhanced vaccine efficacy. However, the original TDEs also contain immune-suppressive proteins. To address this, we proposed a simple yet powerful preconditioning method to improve the overall immunogenicity of the TDEs. This approach involved inducing endoplasmic reticulum (ER) stress on parental tumor cells via N-glycosylation inhibition with tunicamycin. The generated immunogenic TDEs (iTDEs) contained down-regulated immunosuppressive proteins and up-regulated immune adjuvants, effectively activating dendritic cells (DCs) in vitro. Furthermore, in vivo evidence from a tumor-bearing mouse model showed that iTDEs activated DCs, enabling cytotoxic T lymphocytes (CTLs) to target tumors, and eventually established a systemic antitumor immune response. Additionally, iTDEs significantly delayed tumor recurrence in a postsurgery model compared with control groups. These findings highlight the immense potential of our strategy for utilizing TDEs to develop effective cancer vaccines.

Keywords:  cancer vaccine; damage-associated molecular patterns (DAMPs); endoplasmic reticulum (ER) stress; immunogenic extracellular vesicles; tunicamycin

DOI:  https://doi.org/10.1021/acsnano.3c05645
Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.

Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.

  Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.

Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response

DOI:  https://doi.org/10.3390/ijms242417423
Nat Commun. 2023 Dec 15. 14(1): 8364

The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways.

Rayene Berkane, Hung Ho-Xuan, Marius Glogger, Pablo Sanz-Martinez, Lorène Brunello, Tristan Glaesner, Santosh Kumar Kuncha, Katharina Holzhüter, Sara Cano-Franco, Viviana Buonomo, Paloma Cabrerizo-Poveda, Ashwin Balakrishnan, Georg Tascher, Koraljka Husnjak, Thomas Juretschke, Mohit Misra, Alexis González, Volker Dötsch, Paolo Grumati, Mike Heilemann, Alexandra Stolz.

Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator of ER remodeling and essential to maintain cellular homeostasis during environmental changes. We recently showed that members of the FAM134 family play a critical role during stress-induced ER-phagy. However, the mechanisms on how they are activated remain largely unknown. In this study, we analyze phosphorylation of FAM134 as a trigger of FAM134-driven ER-phagy upon mTOR (mechanistic target of rapamycin) inhibition. An unbiased screen of kinase inhibitors reveals CK2 to be essential for FAM134B- and FAM134C-driven ER-phagy after mTOR inhibition. Furthermore, we provide evidence that ER-phagy receptors are regulated by ubiquitination events and that treatment with E1 inhibitor suppresses Torin1-induced ER-phagy flux. Using super-resolution microscopy, we show that CK2 activity is essential for the formation of high-density FAM134B and FAM134C clusters. In addition, dense clustering of FAM134B and FAM134C requires phosphorylation-dependent ubiquitination of FAM134B and FAM134C. Treatment with the CK2 inhibitor SGC-CK2-1 or mutation of FAM134B and FAM134C phosphosites prevents ubiquitination of FAM134 proteins, formation of high-density clusters, as well as Torin1-induced ER-phagy flux. Therefore, we propose that CK2-dependent phosphorylation of ER-phagy receptors precedes ubiquitin-dependent activation of ER-phagy flux.

DOI: https://doi.org/10.1038/s41467-023-44101-5