bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–11–30
thirteen papers selected by
Susan Logue, University of Manitoba
  1. ER stress sparks nerve pain.
  2. Integrin-specific signaling drives ER stress-dependent atherogenic endothelial activation.
  3. Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche.
  4. IRE1 Regulates TOR Signaling via RIDD of RAPTOR1b to Coordinate Growth and Stress Adaptation.
  5. The Unfolded Protein Response-Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention.
  6. Beyond ER Stress: The Pleiotropic Roles of XBP1 in Development and Regeneration.
  7. New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.
  8. Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.
  9. Loss of FAM134B increased endoplasmic reticulum stress and induced cell autophagy in breast cancer.
  10. Protein misfolding and its dual role in neurodegeneration and cancer progression.
  11. Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice.
  12. RB loss sensitizes triple-negative breast cancer to apoptosis induced by cellular stress.
  13. Phosphorylation-coupled autoregulation of TANGO1 and Sec16A maintains functional ER exit sites.
  1. Nat Rev Cancer. 2025 Nov 28.
    ER stress sparks nerve pain.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-025-00896-7
  2. Redox Biol. 2025 Oct 30. pii: S2213-2317(25)00424-0. [Epub ahead of print]88 103911
    Integrin-specific signaling drives ER stress-dependent atherogenic endothelial activation.
    Cyrine Ben Dhaou, Zaki Al-Yafeai, G Ali Cruz-Marquez, Matthew L Scott, Brenna Pearson-Gallion, Elizabeth Cockerham, Hanna Li, Jonette M Peretik, Yuning Hong, Nirav Dhanesha, Arif Yurdagul, Oren Rom, Md Shenuarin Bhuiyan, A Wayne Orr.
      Atherogenic endothelial activation is driven by both the local arterial microenvironment, marked by altered extracellular matrix (ECM) composition and disturbed blood flow, and soluble proinflammatory cues such as oxidized low-density lipoprotein (oxLDL). Fibronectin, a provisional extracellular matrix protein enriched at atheroprone sites, augments these proinflammatory stimuli. Although endoplasmic reticulum (ER) stress is a hallmark of atheroprone regions, its regulation by extracellular matrix and its precise role in endothelial inflammatory activation are not well defined. Here, we show that oxLDL and disturbed flow induce ER stress selectively in endothelial cells adhered to fibronectin, but not in those adhered to basement membrane proteins. This matrix-specific ER stress response requires activation of the integrin family of ECM receptors, as endothelial cells deficient for integrin activation (talin1 L325R mutation) fail to activate ER stress in response to disturbed flow and oxLDL, while direct stimulation of integrins using CHAMP peptides is sufficient to induce ER stress. Silencing fibronectin-binding integrins (α5, αv) using siRNA blocks ER stress induction in vitro, and endothelial-specific deletion of α5 or αv reduces ER stress at atheroprone regions in vivo. Mechanistically, integrin-dependent ER stress is not associated with increased protein synthesis, unfolded protein accumulation, or superoxide production. Scavenging superoxide with TEMPOL does not alleviate ER stress. However, pharmacological inhibition of ER stress using TUDCA suppresses proinflammatory and metabolic gene expression (bulk RNA-seq), without affecting NF-κB activation. Instead, TUDCA prevents activation of the JNK-c-Jun signaling axis, which we show to be essential for proinflammatory gene induction. Blocking this pathway using a JNK inhibitor (SP600125) or dominant-negative c-Jun (TAM67) abrogates inflammatory gene expression following oxLDL or disturbed flow. Together, these findings identify a novel mechanism by which fibronectin-integrin signaling promotes ER stress in response to mechanical and metabolic stressors, amplifying endothelial inflammation through JNK-c-Jun signaling.
    Keywords:  Atherosclerosis; ER stress; Inflammation; Integrin; Oxidized LDL; Shear stress
    DOI:  https://doi.org/10.1016/j.redox.2025.103911
  3. bioRxiv. 2025 Oct 15. pii: 2025.10.15.682539. [Epub ahead of print]
    Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche.
    Bingqing Zou, Qiuyun Chen, Junjun Zheng, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou.
      Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome, yet strategies to enhance lymphocyte regeneration are limited. We studied the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We revealed that PERK activation is a prominent feature of BM endothelium in leukemia patients and is a hallmark response in mouse BM following ionizing irradiation. Ablating endothelial Perk boosted Notch ligand DLL4 expression and promoted DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis shows that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment and niche cytokine production. NOTCH3 is critical for the upregulation of IL7 following irradiation and for supporting the expansion of lymphoid progenitors in mesenchymal sphere cultures. These findings not only unveil a previously unrecognized ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising therapeutic strategy to improve immune recovery after myeloablative transplantation.
    Summary: Zou et al unravel that the adaptive ER stress response in bone marrow blood vessels restricts the post-transplant regeneration of immune progenitor cells by attenuating the expression of Notch ligand DLL4. Targeting ER stress sensor PERK can accelerate immune recovery after transplantation by enhancing DLL4-NOTCH3 signaling and IL7 cytokine production.
    DOI:  https://doi.org/10.1101/2025.10.15.682539
  4. bioRxiv. 2025 Oct 31. pii: 2025.10.30.685559. [Epub ahead of print]
    IRE1 Regulates TOR Signaling via RIDD of RAPTOR1b to Coordinate Growth and Stress Adaptation.
    Brandon C Reagan, Joo Yong Kim, Evan Angelos, Josh V Vermaas, Federica Brandizzi.
      Plant growth and stress resilience depend on integrating diverse signals into coordinated cellular responses. The endoplasmic reticulum (ER) stress sensor IRE1 maintains ER homeostasis and modulates Target of Rapamycin (TOR) signaling. Here, we reveal that TOR misregulation in an ire1ab mutant reduces sensitivity to the stress hormone abscisic acid (ABA), mediated by TOR-dependent phosphorylation of the ABA receptor PYL1. Further, we show that IRE1's endonuclease activity is required for TOR regulation, acting independently of the canonical IRE1/bZIP60 unfolded protein response. Instead, it occurs via Regulated IRE1- Dependent Decay (RIDD) of specific transcripts. We identify RAPTOR1b as a direct RIDD target, establishing a mechanistic link between ER stress sensing and TOR signaling. RIDD- mediated degradation of RAPTOR1b mRNA is required for appropriate ABA responses and stress adaptation. These findings uncover a noncanonical IRE1-TOR signaling axis that fine- tunes growth and stress responses through selective mRNA decay.
    DOI:  https://doi.org/10.1101/2025.10.30.685559
  5. Cancers (Basel). 2025 Nov 13. pii: 3639. [Epub ahead of print]17(22):
    The Unfolded Protein Response-Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention.
    P M Quan Mai, Tam-Anh Truong, Sai Kumar Samala, Bhoomika Muruvekere Lakshmisha, Prapannajeet Biswal, Khadijeh Koushki, Prudhvi Chand Mallepaddi, Geraldine Vijay, Sunil Krishnan.
       BACKGROUND: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER's capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood.
    OBJECTIVES: Here, we critically summarize canonical and non-canonical UPR mechanisms in the contexts of tumor immune microenvironment and lipid metabolism, dissect their crosstalk with other cell fate signaling pathways within cancer, and propose therapeutic strategies to exploit this relationship. We also discuss the fundamental challenges of solely targeting UPR and emphasize the importance of patient stratification, biomarker development, and rational combination therapies to maximize the potential for therapeutic gain. We provide a deconvoluted mechanistic understanding of the UPR process in an attempt to spark prospective clinically relevant therapeutics research.
    Keywords:  ATF6; ER stress and homeostasis; HSPA5; IRE1α; Immunology; PERK; chemotherapy resistance; combination therapy; lipid metabolism; protein folding
    DOI:  https://doi.org/10.3390/cancers17223639
  6. Biomedicines. 2025 Oct 30. pii: 2663. [Epub ahead of print]13(11):
    Beyond ER Stress: The Pleiotropic Roles of XBP1 in Development and Regeneration.
    Delan Huang, Fan Gu, Jingzhi Ma, Zhi Chen.
      This review synthesizes current knowledge on the roles of X-box binding protein 1 (XBP1) in development and regenerative medicine. XBP1 is defined as a key transcription factor that regulates biological processes from embryogenesis to adult tissue homeostasis via both endoplasmic reticulum(ER) stress-dependent and independent mechanisms. Evidence for its regulatory role in cell fate determination and tissue maintenance across multiple systems is presented. The therapeutic potential of targeting XBP1 is explored, particularly for the regeneration of skeletal muscle, skin, and bone. Critical future research priorities are outlined, such as deciphering the precise functions of the Inositol requiring enzyme 1 (IRE1α)/XBP1 signaling axis and evaluating the long-term safety of its modulation. XBP1 is thus confirmed as a prime target for advancing developmental biology and pioneering new regenerative therapies.
    Keywords:  ER stress; XBP1; development; regeneration; tissue homeostasis
    DOI:  https://doi.org/10.3390/biomedicines13112663
  7. Int J Mol Sci. 2025 Nov 08. pii: 10846. [Epub ahead of print]26(22):
    New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.
    Michela Pecoraro, Adele Serra, Maria Julia Lamberti, Maria Pascale, Silvia Franceschelli.
      Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca2+ homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca2+ content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.
    Keywords:  ER stress; corrector; inflammation; misfolding protein; neurodegenerative disease
    DOI:  https://doi.org/10.3390/ijms262210846
  8. Commun Biol. 2025 Nov 24. 8(1): 1650
    Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.
    Aeowynn J Coakley, Adam J Hruby, Jing Wang, Andrew Bong, Tripti Nair, Carmen M Ramos, Athena Alcala, Daniel Hicks, Maxim Averbukh, Naibedya Dutta, Darius Moaddeli, Camilla Pearson, Cynthia J Siebrand, Mattias de Los Rios Rogers, Arushi Sahay, Sean P Curran, Peter J Mullen, Bérénice A Benayoun, Gilberto Garcia, Ryo Higuchi-Sanabria.
      The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissues to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while more modest changes were detected in GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.
    DOI:  https://doi.org/10.1038/s42003-025-09036-1
  9. Front Immunol. 2025 ;16 1652888
    Loss of FAM134B increased endoplasmic reticulum stress and induced cell autophagy in breast cancer.
    Zhaoqi Zhang, Yan Fang, Zhibing Qiu, Shuning Ding, Deyue Liu, Wanqiu Huang, Li Zhu.
       Objective: Breast cancer is a leading cause of cancer-related mortality, and the most prevalent malignant neoplasm amongst women worldwide. This study aimed to explore the role of FAM134B in breast cancer progression.
    Methods: The correlation between FAM134B expression and the prognosis of breast cancer patient was analyzed using the Kaplan-Meier Plotter database. qRT-PCR was used to quantify FAM134B mRNA level, whereas western blotting was employed to detect th expression of FAM134B, autophagy-associated proteins, and endoplasmic reticulum (ER) stress related proteins. Cell proliferation was assessed via CCK-8 and colony formation assays. Cell apoptosis rate was measured by flow cytometry. Autophagosomes formation was observed under a transmission electron microscopy, and the expression of LC3 protein in cells was detected by immunofluorescence. The in vivo function of FAM134B was verified using a tumor xenograft model in nude mice.
    Results: High expression of FAM134B in breast cancer patients was correlated with reduced overall survival and disease-free survival. Both FAM134B mRNA and protein levels were significantly higher in breast cancer cells than normal breast epithelial cells. Downregulation of FAM134B suppressed the proliferation of breast cancer cells and increased their apoptosis rates. Furthermore, silencing FAM134B triggered autophagy and ER stress in breast cancer. In nude mice, FAM134B knockdown also inhibited breast cancer progression and induced autophagy.
    Conclusion: Downregulation of FAM134B inhibited the development of breast cancer through inducing apoptosis, autophagy, and ER stress of breast cancer cells.
    Keywords:  FAM134B; apoptosis; autophagy; breast cancer; endoplasmic reticulum stress
    DOI:  https://doi.org/10.3389/fimmu.2025.1652888
  10. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00088-4. [Epub ahead of print]148 355-377
    Protein misfolding and its dual role in neurodegeneration and cancer progression.
    Rajeshwer Singh Jamwal, Bhawani Sharma, Minerva, Agamya Gupta, Swati Misri, Raju Shankaryan, Ruchi Shah, Rakesh Kumar.
      Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.
    Keywords:  Cancer progression; Molecular chaperones; Neurodegeneration; Protein misfolding; Proteostasis; Ubiquitin–proteasome system (UPS); Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.001
  11. Nat Commun. 2025 Nov 26. 16(1): 10574
    Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice.
    Hugo Lee, Khagani Eynullazada, Qiaodan Ou, Junha Shin, Sushmita Roy, Feyza Engin.
      The unfolded protein response sensor, IRE1α, acts through its regulated IRE1α-dependent decay (RIDD) activity or transcription factor XBP1 to determine cell fate and survival. While blunting RIDD activity prevents diabetes in type 1 diabetes preclinical model non-obese diabetic mice, β-cell-specific function of XBP1 at different stages of disease remains unknown. Here we show that deletion of Xbp1 in β-cells (Xbp1β-/-) of non-obese diabetic mice before insulitis is protective against diabetes. Histological and transcriptomic analyses indicate that following a transient loss of maturity, β-cells of Xbp1β-/- mice exhibit reduced insulitis, apoptosis, and antigenicity phenocopying Ire1αβ-/- mice with no changes in RIDD activity. Comparative transcriptome and regulatory network analyses reveal a largely shared component between the Ire1αβ-/- and Xbp1β-/- mice as well as network components unique to Xbp1β-/-, indicative of IRE1α-independent roles of XBP1. Our findings define the role of β-cell IRE1α/XBP1 and identify previously unrecognized regulatory networks and nodes of this pathway.
    DOI:  https://doi.org/10.1038/s41467-025-65635-w
  12. Cell Death Discov. 2025 Nov 24. 11(1): 543
    RB loss sensitizes triple-negative breast cancer to apoptosis induced by cellular stress.
    Agnieszka K Witkiewicz, Subrahmanya Anirudh Kaligotla Venkata, Erik S Knudsen, Vishnu Kumarasamy.
      Functional loss of RB1 is a common genetic alteration in triple-negative breast cancer (TNBC) and is associated with poor response to targeted therapies, including CDK4/6 inhibitors. In this study, we perform an unbiased drug screen and identify that co-targeting distinct cell cycle processes such as DNA repair and mitosis induce synthetic lethality selectively in RB-deficient models. While RB loss promotes replication stress and mitotic dysregulation, the selective lethality observed with these combinations arises from an alternate mechanism. Under RB-deficient conditions, cells undergo rapid apoptosis in response to cellular stress induced by cell cycle inhibition. This pro-apoptotic response is further augmented by using a pharmacological agent, birinapant that targets XIAP, which is an endogenous inhibitor of the apoptotic pathway. Birinapant in combination with CHK1 or AURKA inhibitors results in selective cell killing in RB-deficient TNBC models and yields durable disease control via apoptosis in vivo. In conclusion, RB loss in TNBC displays an enhanced vulnerability to pro-apoptotic signaling that can enable the effective implementation of new targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41420-025-02864-4
  13. Nat Commun. 2025 Nov 25. 16(1): 10434
    Phosphorylation-coupled autoregulation of TANGO1 and Sec16A maintains functional ER exit sites.
    Miharu Maeda, Masashi Arakawa, Masaki Wakabayashi, Yukie Komatsu, Kota Saito.
      Secretory proteins are synthesized in the endoplasmic reticulum (ER) and begin their transport from specialized domains on the ER called ER exit sites (ERES), where COPII proteins assemble. We previously demonstrated that the interaction between TANGO1 and Sec16A is critical for ERES formation. In this study, we reveal that the phosphorylation of TANGO1 and Sec16A is regulated by a FAM83A/CK1α-mediated negative feedback loop. Conversely, their dephosphorylation is regulated in a spatially distinct manner by different phosphatase complexes: PPP6R3/PPP6C for Sec16A and PPP1R15B/PPP1C for TANGO1. Excessive phosphorylation of either TANGO1 or Sec16A leads to ERES disassembly, while excessive dephosphorylation impairs secretion. Our findings demonstrate that maintaining a balanced phosphorylation state of TANGO1 and Sec16A through autoregulation by FAM83A/CK1α and the phosphatases PP1 and PP6 is essential for sustaining proper secretory activity at the ERES.
    DOI:  https://doi.org/10.1038/s41467-025-65409-4
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