bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–09–28
nine papers selected by
Susan Logue, University of Manitoba
  1. Targeting the Unfolded Protein Response with Natural Products: Therapeutic Potential in ER Stress-Related Diseases.
  2. The SARS-CoV-2 spike protein interacts with HAX1 to modulate cellular stress responses through activation of the UPR.
  3. Decoding the Impact of Lipid Saturation on ER Signaling Networks, ERSU, UPR, and ERAD.
  4. Endoplasmic reticulum stress in lung cancer.
  5. The shutdown of food digestion due to endoplasmic reticulum homeostasis disruption acts as a protective mechanism in C. elegans.
  6. Generating a Cell Model to Study ER Stress in iPSC-Derived Medium Spiny Neurons from a Patient with Huntington's Disease.
  7. Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models.
  8. Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing.
  9. PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules independent of its kinase activity.
  1. Int J Mol Sci. 2025 Sep 10. pii: 8814. [Epub ahead of print]26(18):
    Targeting the Unfolded Protein Response with Natural Products: Therapeutic Potential in ER Stress-Related Diseases.
    Simona Martinotti, Elia Ranzato.
      This review delves into the intricate relationship between ER stress, the UPR, and human disease, with a specific focus on the therapeutic potential of natural products. We classify and discuss a wide range of natural compounds based on their unique mechanisms of action, whether they act as UPR inhibitors, activators, or indirectly alleviate ER stress by reducing oxidative burden or improving protein folding. By synthesizing the current literature, this review aims to provide a valuable resource for researchers and clinicians, highlighting the most promising natural products and their potential for development into novel therapeutic agents for treating pathologies driven by ER stress.
    Keywords:  ER stress; natural products; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/ijms26188814
  2. FEBS J. 2025 Sep 21.
    The SARS-CoV-2 spike protein interacts with HAX1 to modulate cellular stress responses through activation of the UPR.
    Tony Avril, Elodie Lafont.
      During cell infection, viruses maintain the lifespan of host cells by preserving key functions of cellular organelles such as the endoplasmic reticulum (ER) and mitochondria to guarantee protein secretion and energy production. The host secretory pathway is rapidly hijacked to produce viral proteins and reconstitute viral particles for further viral dissemination. However, secreted protein synthesis and proper folding are tightly regulated in the host ER to maintain homeostasis, otherwise this organelle is subjected to ER stress that triggers an adaptive response named the unfolded protein response (UPR). The UPR first aims at restoring ER function by producing enzymes to correct or eliminate misfolded proteins. If ER stress remains unresolved, the UPR triggers cell death. In the work published by Zhu et al. in this issue of The FEBS Journal, the authors explore a previously undescribed molecular hijacking function of SARS-CoV-2 to limit host cell death. Indeed, the viral spike protein directly interacts with the host HAX1 molecule to promote UPR activation, limiting the production of deleterious reactive oxygen species and mitochondrial dysfunction to maintain host cell survival.
    Keywords:  ER stress; HAX1; ROS production; SARS‐CoV‐2; cell death; spike
    DOI:  https://doi.org/10.1111/febs.70259
  3. bioRxiv. 2025 Sep 17. pii: 2025.09.15.676312. [Epub ahead of print]
    Decoding the Impact of Lipid Saturation on ER Signaling Networks, ERSU, UPR, and ERAD.
    Xia Li, Maho Niwa.
      The faithful inheritance of a functional endoplasmic reticulum (ER) in Saccharomyces cerevisiae is safeguarded by the ER Stress Surveillance (ERSU) checkpoint, which delays cytokinesis when ER homeostasis is perturbed. Under stress, ER transmission to the daughter cell is halted, while in parallel-but through independent pathways-the Unfolded Protein Response (UPR) restores ER function and ER-associated degradation (ERAD) eliminates misfolded proteins, ultimately allowing cell cycle re-entry. ER stress also transiently stimulates sphingolipid biosynthesis, with the intermediate phytosphingosine (PHS) acting as a key activator of ERSU. Yet, how broader lipid parameters-such as membrane composition, saturation, and fluidity-reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To address this, we employed a tightly controlled experimental system to selectively alter lipid saturation and phospholipid composition while monitoring ER inheritance within the framework of ER homeostasis maintained by UPR and ERAD. Strikingly, we found that perturbations in lipid balance exerted specific effects on ER inheritance that were distinct from their impact on UPR and ERAD. These findings reveal lipid homeostasis as a critical integrator of ER functional regulation, linking ERSU, UPR, and ERAD into a unified adaptive network that ensures robust ER transmission and cellular resilience under stress.
    DOI:  https://doi.org/10.1101/2025.09.15.676312
  4. Front Oncol. 2025 ;15 1550075
    Endoplasmic reticulum stress in lung cancer.
    Donghuan Zhang, Lanlan Lin, Hui Jin, Huajun Mao, Luying Wang, Wenwen Ma, Zhenghong Lao.
      Endoplasmic reticulum is the primary site of eukaryotic cells involved in biosynthesis, lipid metabolism, glucose metabolism, protein folding and secretion. Multiple factors in the tumor microenvironment may induce the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum and trigger endoplasmic reticulum (ER) stress. Adaptive mechanisms including unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) are activated in response to ER stress. Previous studies have revealed that ER stress may participate in epithelial mesenchymal transformation, apoptosis, metabolic regulation and drug resistance of lung cancer cells. Herein, we summarized the potential effects and regulatory mechanisms of ER stress on the biological process of lung cancer, which may provide scientific significance and clinical value for elucidating the adaptability of lung cancer cells under stress and developing novel targeted therapies.
    Keywords:  endoplasmic reticulum stress; lung cancer; targeted therapy; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.3389/fonc.2025.1550075
  5. Nat Commun. 2025 Sep 25. 16(1): 8417
    The shutdown of food digestion due to endoplasmic reticulum homeostasis disruption acts as a protective mechanism in C. elegans.
    YongJuan He, Yunqing Zhang, Huijuan Xie, Zhao Shan, Zongliu Hou, Bin Qi.
      Food digestion is essential for nutrient absorption, supporting protein synthesis and maintaining endoplasmic reticulum (ER) homeostasis. However, whether animals can sense ER stress and suppress digestion to reduce ER overload remains unclear. Here, we show that Caenorhabditis elegans can sense ER stress and shut down digestion as a protective response. Food intake activates the unfolded protein response in the ER, and loss of its central regulator, XBP-1, impairs digestion, highlighting the importance of ER homeostasis in food digestion. We identify FDR-1, a food-induced protein, as a key factor that promotes digestion by preserving ER balance through its interaction with DPY-11. Disruption of FDR-1 triggers the innate immune p38/PMK-1 pathway, leading to a protective shutdown of digestion to mitigate ER stress. These findings reveal an adaptive mechanism by which animals limit digestion under ER stress and suggest that modulating nutrient intake may offer therapeutic strategies for diseases related to ER dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-63712-8
  6. Int J Mol Sci. 2025 Sep 13. pii: 8930. [Epub ahead of print]26(18):
    Generating a Cell Model to Study ER Stress in iPSC-Derived Medium Spiny Neurons from a Patient with Huntington's Disease.
    Vladlena S Makeeva, Anton Yu Sivkov, Suren M Zakian, Anastasia A Malakhova.
      iPSCs and their derivatives are used to investigate the molecular genetic mechanisms of human diseases, to identify therapeutic targets, and to screen for small molecules. Combining technologies for generating patient-specific iPSC lines and genome editing allows us to create cell models with unique characteristics. We obtained and characterized three iPSC lines by reprogramming peripheral blood mononuclear cells of a patient with Huntington's disease (HD) using episomal vectors encoding Yamanaka factors. iPSC lines expressed pluripotency marker genes, had normal karyotypes and were capable of differentiating into all three germ layers. The obtained iPSC lines are useful for modeling disease progression in vitro and studying pathological mechanisms of HD, such as ER stress. A transgene of genetically encoded biosensor XBP1-TagRFP was introduced into the iPSCs to visualize ER stress state of cells. The study demonstrated that iPSC-derived medium spiny neurons develop ER stress, though the IRE1-mediated pathway does not seem to be involved in the process.
    Keywords:  ER stress; Huntington’s disease; XBP1-TagRFP biosensor; iPSC-based cell model; iPSC-derived medium spiny neurons
    DOI:  https://doi.org/10.3390/ijms26188930
  7. Sci Rep. 2025 Sep 26. 15(1): 33070
    Targeting ATF6 reduces pathological neovascularization and improves visual outcomes in retinal disease models.
    Allyssa Bradley, Soyoung Park, Soyeon Park, Kyle Kim, Angela Galdamez, Hyejung Min, Monica Sophia Diaz-Aguilar, M Elizabeth Hartnett, Eun-Jin Lee, Jonathan H Lin.
      Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by ER stress and upregulates many proteins, including angiogenesis factors like VEGF and HIF-1α. This suggests that UPR genes and pathways may drive retinal angiogenesis. Here, we tested the role of the UPR regulator Activating Transcription Factor 6 (ATF6) in pathological and developmental retinal angiogenesis. We induced pathological retinal neovascularization in Atf6-/- mice using the oxygen-induced retinopathy (OIR) model and found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR transcriptional program induction. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppressed retinal expression of UPR genes. Additionally, in postnatal day 7 Atf6-/- mice when the retinal vasculature is developing in response to physiologic intraocular hypoxia, there was a transient but significant defect in pruning and retinal blood vessel extension. Together, our results demonstrate ATF6's causal role in developmental and pathological retinal angiogenesis and highlight its potential as a therapeutic target to preserve vision in retinal neovascularization diseases.
    DOI:  https://doi.org/10.1038/s41598-025-15393-y
  8. Nat Commun. 2025 Sep 26. 16(1): 8531
    Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing.
    Yang Liu, Amrutha K Avathan Veettil, Raphael Gasper, Mao Jiang, Leon Wagner, Oguz Hastürk, Peng Wu.
      The inositol-requiring enzyme 1 alpha (IRE1α) is an important sensor protein with dual kinase and ribonuclease function. It induces X-box binding protein 1 (XBP1) mRNA splicing and mediates endoplasmic reticulum (ER) stress-triggered downstream unfolded protein response signaling pathways. The dysregulation of IRE1α has been associated with multiple human diseases, and thus IRE1α-targeting small molecules harbor great therapeutic potential. We herein report a series of substituted indoles as IRE1α inhibitors (such as IA107) of excellent potency and selectivity. We also report a resolved co-crystal structure that reveals a unique inhibition mode of IA107 that allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization. The following cellular evaluation results demonstrate that IA107 concentration-dependently inhibits the cellular ER stress-induced XBP1 mRNA splicing, and the ester-containing prodrug exhibits a ~ 50-fold increase in cellular activity. Collectively, our results establish the indoles as a potent and selective IRE1α-inhibiting chemotype that modulates RNA splicing and expands the biological application potential associated with IRE1α targeting via small molecules.
    DOI:  https://doi.org/10.1038/s41467-025-64291-4
  9. Mol Biol Cell. 2025 Sep 24. mbcE25060277
    PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules independent of its kinase activity.
    Miguel Barriera Diaz, Kirk A Staschke, Anthony J Baucum, Dan F Spandau, Ronald C Wek.
      Successful cutaneous wound healing requires re-epithelialization by keratinocytes using a coordinated migratory process called keratinocyte collective cell migration (KCCM). Environmental stresses such as wounding induce the Integrated Stress Response (ISR) initiated by protein kinases that phosphorylate the α subunit of eIF2 and mitigate translational control to alleviate stress damage. We previously reported that the ISR protein kinase GCN2 (EIF2AK4) facilitates KCCM via sustained phosphorylation of eIF2α and coordinated production of reactive oxygen species and amino acid transport. In this study, we show that a second ISR protein kinase PERK (EIF2AK3) also contributes to KCCM. PERK promotes KCCM by protein-protein interactions requiring the cytoplasmic portion of PERK but independent of its catalytic functions. To discern these PERK interactions, we used BioID proximity labeling, immunoprecipitation analyses, and immunofluorescence microscopy to show that PERK interacts with multiple cell adhesion and cytoskeletal complexes important for KCCM. PERK engages with the hemidesmosome proteins ITGA6, ITGB4, COLXVII, and the desmosome proteins JUP, DSG2, and DSG3. Loss of PERK disrupts expression and localization of these cell adhesion proteins, which alters keratinocyte morphology and increases cell-substrate and intercellular adhesions. Our results define an underappreciated scaffolding function for PERK involving cell adhesions that are critical for KCCM.
    DOI:  https://doi.org/10.1091/mbc.E25-06-0277
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒05 at 19:28.