bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–03–30
seven papers selected by
Susan Logue, University of Manitoba
  1. Cell Homeostasis or Cell Death-The Balancing Act Between Autophagy and Apoptosis Caused by Steatosis-Induced Endoplasmic Reticulum (ER) Stress.
  2. Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
  3. Soman induces endoplasmic reticulum stress and apoptosis of cerebral organoids via the GRP78-ATF6-CHOP signaling pathway.
  4. Modulation of Ire1-Xbp1 Defense Pathway in Encephalomyocarditis Virus-Infected HeLa Cells.
  5. Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
  6. Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.
  7. Endoplasmic Reticulum-Dependent Apoptotic Response to Cellular Stress in Patients with Rheumatoid Arthritis.
  1. Cells. 2025 Mar 18. pii: 449. [Epub ahead of print]14(6):
    Cell Homeostasis or Cell Death-The Balancing Act Between Autophagy and Apoptosis Caused by Steatosis-Induced Endoplasmic Reticulum (ER) Stress.
    Anna Stilkerich, Gerda Schicht, Lena Seidemann, René Hänsel, Adrian Friebel, Stefan Hoehme, Daniel Seehofer, Georg Damm.
      Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.
    Keywords:  ER stress; MASLD; hepatic lipid metabolism; liver regeneration; primary human hepatocytes; unfolded protein response
    DOI:  https://doi.org/10.3390/cells14060449
  2. Mol Metab. 2025 Mar 20. pii: S2212-8778(25)00035-3. [Epub ahead of print] 102128
    Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
    L Stilgenbauer, Q Chen, D Pungi, N James, H Jayarathne, L Koshko, S Scofield, K Zhang, M Sadagurski.
       BACKGROUND: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.
    OBJECTIVES: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.
    METHODS: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.
    RESULTS: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.
    CONCLUSIONS: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.
    Keywords:  ER stress; Hypothalamic inflammation; Hypothalamus; Microglia; Neuroinflammation; UPR
    DOI:  https://doi.org/10.1016/j.molmet.2025.102128
  3. FEBS Open Bio. 2025 Mar 28.
    Soman induces endoplasmic reticulum stress and apoptosis of cerebral organoids via the GRP78-ATF6-CHOP signaling pathway.
    Yue Wei, Zhanbiao Liu, Jingjing Shi, Qian Jin, Wenqian Chen, Xuejun Chen, Liqin Li, Hui Chen.
      Soman is an organophosphorus compound that induces neurotoxicity. In addition to its direct toxic effects resulting from acetylcholine accumulation, neurotoxicity may also be exacerbated by inducing endoplasmic reticulum (ER) stress. In light of the current scarcity of appropriate in vitro assessment models, in the present study, we used cerebral organoids derived from human pluripotent stem cells, a new tool for investigating the mechanisms of neurotoxicity, to investigate soman-induced ER stress. The results demonstrated that soman significantly suppressed acetylcholinesterase activity and activated the GRP78-ATF6-CHOP (i.e. glucose-regulated protein 78-activating transcription factor 6-C/EBP homologous protein) ER stress cascade, driving apoptosis in cerebral organoids. Pharmacological inhibition of ER stress by pre-treating cerebral organoids with the ER stress inhibitor 4-phenylbutyric acid prior to soman exposure attenuated apoptotic signaling and downregulated GRP78, ATF6 and CHOP expression. Parallel in vivo validation utilized a rat model with subcutaneous soman exposure, focusing on hippocampal and striatal ER stress markers. Consistent with the in vitro findings, soman-exposed rats exhibited marked ER stress activation in brain regions critical for neurotoxicity. This study establishes ER stress as a key contributor to soman-induced neurotoxicity and highlights cerebral organoids as a physiologically relevant model for organophosphorus compound research. We propose ER stress modulation as a potential therapeutic strategy to mitigate neurotoxic outcomes.
    Keywords:  ATF6; ER stress; cerebral organoids; organophosphates; soman
    DOI:  https://doi.org/10.1002/2211-5463.70027
  4. Viruses. 2025 Mar 02. pii: 360. [Epub ahead of print]17(3):
    Modulation of Ire1-Xbp1 Defense Pathway in Encephalomyocarditis Virus-Infected HeLa Cells.
    Anna Shishova, Yury Ivin, Ekaterina Gladneva, Ksenia Fominykh, Ilya Dyugay, Anatoly Gmyl.
      A key contributor to the pathogenicity of viruses is their interaction with cellular defense mechanisms, including UPR (unfolded protein response) that counteracts the accumulation of misfolded proteins in the endoplasmic reticulum (known as ER stress). One of the UPR branches is mediated by the IRE1 (inositol-requiring enzyme 1) protein, which possesses protein kinase and RNase activities that facilitate the unconventional cytoplasmic splicing of XBP1 mRNA, leading to the upregulation of the XBP1 transcription factor. In this study, we demonstrate that Encephalomyocarditis Virus (Cardiovirus rueckerti) is able to suppress IRE1-dependent XBP1 activation. HeLa cells infection with EMCV resulted in the modulation of phosphorylated IRE1 levels throughout the infection cycle. Viral infection did not result in the accumulation of spliced XBP1 mRNA. Moreover, the addition of a chemical inducer of ER stress (dithiothreitol) to infected cells led to a markedly lower accumulation of spliced XBP1 mRNA as compared to the level of this mRNA in inducer-treated mock-infected cells. Thus, our results demonstrate the ability of picornaviruses to modulate another defensive activity of the host cell.
    Keywords:  ER stress; IRE1; UPR; XBP1; encephalomyocarditis virus; unconventional splicing
    DOI:  https://doi.org/10.3390/v17030360
  5. J Cell Biol. 2025 May 05. pii: e202405060. [Epub ahead of print]224(5):
    Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
    Yazhen Huo, Xinlu Liu, Chen Lu, Tao Li, Zaili Yang, Fenfen Xu, Si Chen, Kailin Yin, Likun Wang.
      Under endoplasmic reticulum (ER) stress (ERS), cells initiate the unfolded protein response (UPR) to maintain ER homeostasis. Recent studies revealed ERS transmission between cells and tissues, by activating the cell-nonautonomous UPR in cells that do not experience ERS directly. Here, we report that ERS triggers a rapid release of ceramide independent of the UPR, but requiring the acid sphingomyelinase activity. Carried by lipoproteins, ceramide is delivered to receiving cells to induce the UPR and regulate cell functions at multiple aspects, including lipid accumulation, cell death, and cytokine production. Mechanistically, extracellular ceramide stimulates ceramide synthesis at the transcription level in receiving cells, leading to ceramide accumulation in the ER so as to reduce membrane fluidity to disrupt ER calcium homeostasis, thus activating the UPR. Sphingomyelin counterbalanced the effect of ceramide. UPR induction is the frontline response to protect cells from ceramide insult. Our study suggests ceramide-mediated ERS transmission as a universal cell-cell communication model regulating a wide range of physiological events.
    DOI:  https://doi.org/10.1083/jcb.202405060
  6. RSC Med Chem. 2025 Mar 18.
    Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.
    Breanna L Zerfas, Yingpeng Liu, Jianwei Che, Katherine A Donovan, John M Hatcher, Fidel Huerta, Rebecca J Metivier, Radosław P Nowak, Leah Ragosta, Tiffany Tsang, Eric S Fischer, Lyn H Jones.
      IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or kinase domains of the enzyme have limited utility and targeted degradation would address additional scaffolding functions of the protein. Here, we describe the design and development of IRE1α proteolysis targeting chimeras (PROTACs) based on a lysine-reactive salicylaldehyde RNase inhibitor, and present the structure-activity relationships (SARs) that delivered the first highly selective degraders of a native ER-membrane associated protein. Medicinal chemistry optimization exploited ternary complex computational modelling to inform design, HiBiT-SpyTag IRE1α degradation and NanoBRET cereblon occupancy cell-based assays to generate SARs, and mass spectrometry-based proteomics to assess broad selectivity in an unbiased manner. Merging IRE1α and CRBN ligand chemotypes provided the truncated chimera CPD-2828 with physicochemical properties more akin to an oral molecular glue degrader than a traditional PROTAC.
    DOI:  https://doi.org/10.1039/d5md00028a
  7. Int J Mol Sci. 2025 Mar 11. pii: 2489. [Epub ahead of print]26(6):
    Endoplasmic Reticulum-Dependent Apoptotic Response to Cellular Stress in Patients with Rheumatoid Arthritis.
    Aleksandra Kucharska-Lusina, Maciej Skrzypek, Agnieszka Tokarczyk, Grzegorz Dragan, Ireneusz Majsterek.
      Rheumatoid arthritis (RA) is a chronic, common autoimmune disease. It is characterized by inflammatory polyarthritis, which can lead to permanent disability in patients. Current treatment is mainly symptom-related, aiming to reduce pain and inflammation, but does not lead to a full recovery. This treatment includes non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). It has been shown that, due to chronic inflammation, reduced glucose levels and hypoxia, endoplasmic reticulum (ER) stress is induced in RA patients, leading to the activation of multiple signaling pathways, including the ER-dependent adaptation of the unfolded protein response (UPR) pathway. The aim of this study was to assess the level of apoptosis in patients diagnosed with RA. The study sought to investigate whether UPR response correlated with apoptosis induction could serve as a potential diagnostic marker or therapeutic target. In vitro studies have shown that UPR pathway activity can be observed in patients diagnosed with RA. The study group consisted of PBMC cells from 61 individuals, including a total of 31 rheumatoid arthritis patients and 30 healthy controls. In order to validate UPR activation, we estimated molecular markers of ER stress via RT-qPCR expression analysis. GAPDH expression was used as a standard control. Elevated levels of mRNA for the eIF2α (p-value = 0.001903), the BBC3 (PUMA) (p-value = 0.007457 × 10-7) and the TP53 (p-value = 0.002212) were confirmed in a group of RA patients. Further analysis showed that after the induction of apoptosis the percentage of DNA contained in the tail was 37.78% higher in RA patients than in the control group (p-value = 0.0003) measured by comet assay. The exogenous damage caused by hydrogen peroxide was found to be statistically elevated in RA patients and the caspase-3 level was calculated of 40.17% higher than in controls (p-value = 0.0028). It was also found that PBMC cells from RA patients were more sensitive to apoptotic induction. Our results were confirmed by flow cytometry. The most important finding from our data was the confirmation of elevated sensitivity to apoptosis induction in RA patients; the results showed a 40.23% higher percentage of cells in early apoptosis than in the control group (p-value = 0.0105). Our results may help to assess the feasibility of the application of early diagnosis and targeted therapy in the treatment of RA patients, including the ER signaling pathway via selected UPR-dependent molecular inhibitors.
    Keywords:  PERK; apoptosis; endoplasmic reticulum stress; rheumatoid arthritis; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms26062489
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