bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–06–28
twelve papers selected by
Susan Logue, University of Manitoba
  1. Inhibition of AGR2 triggers secretion of GRP78 and sensitizes gastroesophageal junction adenocarcinoma cells to ER stress.
  2. Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy.
  3. Targeting endoplasmic reticulum stress: a novel therapeutic strategy for neuropathic pain.
  4. Sex Differences in ER Stress Pathways Are a Key Determinant of β-Cell Proliferation and Resilience.
  5. 1-Deoxysphingolipids Require Very-Long-Chain Ceramide Synthesis to Induce ER Stress and Cytotoxicity.
  6. Exosomal misfolded α1-antitrypsin triggers a cytosolic GRP78-dependent unfolded protein response and pro-survival signaling in pre-metastatic tissues.
  7. ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
  8. Osajin attenuates diazinon-induced pulmonary toxicity in rats.
  9. Inhibition of KDEL Receptors Remodels the Tumor Microenvironment for T Cell Independent Tumor Regression.
  10. PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
  11. IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
  12. Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.
  1. Biochem Biophys Res Commun. 2026 Jun 20. pii: S0006-291X(26)00945-9. [Epub ahead of print]829 154181
    Inhibition of AGR2 triggers secretion of GRP78 and sensitizes gastroesophageal junction adenocarcinoma cells to ER stress.
    Quentin Bourgery, Nathalie Martin, Clémentine De Schutter, Stéphanie Flament, Fabrice Bray, Olivier Pluquet.
      The endoplasmic reticulum (ER) chaperone Anterior Gradient 2 (AGR2) is overexpressed in various adenocarcinomas, promoting tumor progression and chemoresistance. However, its exact role in modulating the Unfolded Protein Response (UPR) and remodeling the cancer cell secretome under proteotoxic stress remains poorly understood. Using shRNA-mediated silencing of AGR2 combined with high-throughput LC-MS/MS proteomic analysis in OE19 gastroesophageal junction adenocarcinoma cells, we profiled the global changes in protein secretion under basal and tunicamycin-induced ER stress conditions. Proteomic screening identified 75 differentially secreted proteins, with AGR2 depletion triggering a widespread up-secretion phenotype. Bioinformatic analysis revealed enrichment in pathways related to glycolysis, antigen processing and presentation, and extracellular matrix components. Notably, the ER-resident chaperone GRP78 was identified as a critical hub protein within the secretome. AGR2 knockdown downregulated intracellular GRP78 expression, and compromised UPR activation. Under ER stress, the absence of AGR2 triggered a massive secretion of GRP78 in the extracellular space, which correlated with a significantly increased sensitivity to tunicamycin-induced cell death. These findings identify AGR2 as a key regulator of GRP78 proteostasis and ER retention. By controlling the balance between intracellular retention and extracellular release of GRP78, AGR2 supports adaptive ER stress response and may contribute to tumor cell survival in gastroesophageal junction adenocarcinoma.
    Keywords:  AGR2 (Anterior gradient 2); ER stress; GRP78 (HSPA5); Secretome
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154181
  2. Pharmaceuticals (Basel). 2026 Jun 15. pii: 941. [Epub ahead of print]19(6):
    Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy.
    Ovanes Muradyan, Moudood Tahir, Victoria Sarafian.
      Targeted synergistic therapies represent a rapidly developing branch of oncology. The emergence of novel targeting agents allows for modulation of an ever-larger set of cellular pathways. The Unfolded Protein Response (UPR) is a key element of cellular proteostasis that is significantly hyperactivated in a wide range of cancer cell types, especially those with high secretory activity. As cancer cells are especially vulnerable to endoplasmic reticulum stress (ER Stress), they become heavily dependent on UPR function to maintain homeostasis. A wide number of pharmacologic agents can stimulate the UPR and shift it from its initial pro-survival phase to the terminal pro-apoptotic phase. Key strategies include the use of UPR feedback inhibitors (e.g., GRP78 antagonists), direct pathway inhibitors targeting the PERK or IRE1α branches, and signal pathway modulators (e.g., TKIs and BTK inhibitors) that indirectly exacerbate proteotoxic stress. In this study we provide a mechanistic framework where we classify synergistic therapies based on their mechanism of action and explore how they influence ER Stress and UPR activation. Evidence synthesized from these studies suggests that synergistic combinations can overcome therapeutic resistance and selectively induce apoptosis in cancer cells characterized by high proteotoxic stress.
    Keywords:  ER stress; UPR; cancer cells; proteasome inhibitors; synergistic therapies
    DOI:  https://doi.org/10.3390/ph19060941
  3. Front Pain Res (Lausanne). 2026 ;7 1761647
    Targeting endoplasmic reticulum stress: a novel therapeutic strategy for neuropathic pain.
    Yang Niu, Jiayu Han, Tao Song, Xueshu Tao.
      Neuropathic pain (NP) is a chronic and debilitating condition arising from lesions or diseases of the somatosensory system. Increasing evidence identifies endoplasmic reticulum (ER) stress as a central mechanism contributing to NP pathogenesis. Activation of the unfolded protein response disrupts cellular homeostasis and promotes many pathological processes, including neuroinflammation, oxidative stress, apoptosis, and ferroptosis. Notably, ER stress signaling exhibits strong cell-type specificity, affecting neurons, glial cells, and immune cells across both peripheral and central nervous systems. Targeting ER stress has therefore emerged as a promising therapeutic strategy. However, ER stress signaling remains complex, and clinical translation is still limited. This review summarizes current mechanisms and highlights emerging ER stress-targeted therapies for NP.
    Keywords:  endoplasmic reticulum stress; neuroinflammation; neuropathic pain; phytochemicals; unfolded protein response
    DOI:  https://doi.org/10.3389/fpain.2026.1761647
  4. Diabetes. 2026 Jul 01. 75(7): 1083-1085
    Sex Differences in ER Stress Pathways Are a Key Determinant of β-Cell Proliferation and Resilience.
    Sing-Young Chen, Elizabeth J Rideout, James D Johnson.
      
    DOI:  https://doi.org/10.2337/dbi26-0012
  5. J Biol Chem. 2026 Jun 20. pii: S0021-9258(26)02153-8. [Epub ahead of print] 113281
    1-Deoxysphingolipids Require Very-Long-Chain Ceramide Synthesis to Induce ER Stress and Cytotoxicity.
    Colleen Byrnes, Benjamin A Clarke, Hongling Zhu, Y Terry Lee, Saurav Majumder, Mari Kono, Richard L Proia.
      Sphingolipids play key roles in cellular systems both as membrane components and as signaling molecules. Their biosynthesis, which occurs in the endoplasmic reticulum (ER), begins with the condensation of an amino acid, typically serine, and a fatty acyl-CoA. Under certain pathological conditions, alanine can be substituted for serine in the condensation reaction, producing 1-deoxysphingolipids, which lack the 1-hydroxyl group on the sphingoid base. Unlike typical sphingolipids, 1-deoxysphingolipids are unable to accept a head group modification, which alters their metabolic processing and prevents their canonical degradation. The accumulation of these "headless" 1-deoxysphingolipids causes neurotoxicity in various neurological and metabolic disorders. Here, we conducted a genome-wide CRISPR-Cas9 screen to identify pathways leading to 1-deoxysphinganine-induced toxicity in SH-SY5Y cells, a model used to study neurotoxic responses. Our top genetic hits highlighted the pathway involved in synthesizing ceramides with very-long-chain fatty acids (C22-C26). Using CRISPR-Cas9-modified SH-SY5Y cells with loss-of-function (LOF) mutations in the TECR or CERS2 genes-both critical for producing very-long-chain ceramides-we validated that this pathway was essential for 1-deoxysphinganine-mediated toxicity. Furthermore, we demonstrated that the ceramide synthesis pathway is required for 1-deoxysphinganine to trigger ER stress, as evidenced by significantly increased expression of the unfolded protein response in WT, but not TECR or CERS2 LOF mutant, SH-SY5Y cells exposed to 1-deoxysphinganine. Collectively, the data support a model in which ceramide synthase-dependent conversion of 1-deoxysphinganine to very-long-chain 1-deoxyceramide species is required for full ER-stress induction and cytotoxicity. The findings highlight potential therapeutic targets for neuropathological diseases caused by 1-deoxysphingolipid accumulation.
    Keywords:  1-deoxysphingolipids; endoplasmic reticulum stress (ER stress); fatty acid; fatty acid metabolism; lipid metabolism; lipotoxicity; sphingolipid; very-long-chain ceramides
    DOI:  https://doi.org/10.1016/j.jbc.2026.113281
  6. J Biol Chem. 2026 Jun 20. pii: S0021-9258(26)02154-X. [Epub ahead of print] 113282
    Exosomal misfolded α1-antitrypsin triggers a cytosolic GRP78-dependent unfolded protein response and pro-survival signaling in pre-metastatic tissues.
    Anuran Bhattacharya, Tiyasa Saha, Aditya Shukla, Ananya Banerjee, Himansu Roy, Urmi Chatterji.
      Tumor-derived exosomes (TDEs) promote cancer progression by transmitting oncogenic signals to adjacent cells. However, their impact on distant, non-malignant tissues remains poorly defined, particularly with respect to their bioactive cargo. Subsequently, a misfolded form of α1-antitrypsin (mA1AT) was identified as an exosomal component secreted by 4T1 mice mammary tumor cells, and validated in breast cancer patient serum. Exosome-mediated delivery of mA1AT to healthy lung, liver and bone marrow cells, prospective sites for metastasis, induces cytoplasmic expression of GRP78, triggers a pro-survival unfolded protein response (UPR), activates proliferation and inflammation, while suppressing apoptosis, both in vitro and in vivo. In silico modeling and co-immunoprecipitation confirm interaction between GRP78 and mA1AT, implicating non-canonical UPR activation. Depletion of mA1AT from exosomes reduces these effects, signifying its role in exosome-mediated transfer of oncogenic traits to distant, non-malignant tissues, and highlighting its potential as a therapeutic target to limit systemic dissemination of tumorigenic cues. Statement of significance (a one- or two-sentence summary of the manuscript's salient findings) 50 words Tumor-derived exosome-borne misfolded A1AT confers tumorigenic traits to healthy organs prone to metastasis, prior to arrival of circulating tumor cells, by enhancing proliferation, inflammation and activating cellular stress via increased interaction with GRP78 in the cytosol. Misfolded A1AT can be developed as a diagnostic and therapeutic molecule for tumor metastasis.
    Keywords:  ER stress; GRP78; Inflammation; Stemness; Tumor-derived exosomes; Unfolded Protein Response; misfolded α1-antitrypsin
    DOI:  https://doi.org/10.1016/j.jbc.2026.113282
  7. Nucleic Acids Res. 2026 Jun 22. pii: gkag641. [Epub ahead of print]54(12):
    ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
    Jung-Sik Joo, Mikyoung Kim, Sugyung Kim, Hyejin Kim, Hyoung-Pyo Kim.
      Endoplasmic reticulum (ER) stress triggers transcriptional programs that promote either adaptation or apoptosis, yet the epigenetic mechanisms underlying this response remain incompletely understood. Here, integrated multi-omics analyses of unfolded protein response transcription factor knockout cells identify ATF4 as a dominant regulator of ER stress-responsive enhancer activation and chromatin looping. Loss of ATF4 markedly impairs stress-induced H3K27ac accumulation and enhancer-promoter interactions at ATF4-associated regulatory elements, establishing ATF4 as a central organizer of the stress-responsive regulatory landscape. We further identify CHOP as a key functional partner of ATF4 during ER stress. Integrative analyses of ATF4 occupancy and H3K27ac landscapes in CHOP-knockout cells reveal that CHOP selectively modulates ATF4-dependent enhancer activity and controls distinct subsets of stress-responsive genes. This cooperation preferentially promotes apoptosis-associated transcriptional programs while having limited effects on core adaptive responses. Together, our findings define a hierarchical regulatory framework in which ATF4 establishes enhancer activation and chromatin looping networks, whereas CHOP selectively diversifies their output to specify ER stress-responsive gene programs.
    DOI:  https://doi.org/10.1093/nar/gkag641
  8. Tissue Cell. 2026 Jun 22. pii: S0040-8166(26)00417-9. [Epub ahead of print]103 103723
    Osajin attenuates diazinon-induced pulmonary toxicity in rats.
    İlyas Bozkurt, Esra Aktaş Şenocak, Tuba Karaarslan, Ömercan Alat, Cihan Gür, Volkan Ay, Mustafa İleriturk, İsmail Can, Mesut Bünyami Halıcı.
      Diazinon (DZN) is an organophosphate insecticide whose widespread agricultural and veterinary use raises continuing concerns about non-target organ toxicity. While its hepatic and neurological effects have been extensively documented, the molecular basis of DZN-induced pulmonary injury - and whether plant-derived isoflavones can counteract it - remains poorly defined. The present study examined the lung-protective potential of Osajin (OSJ), an isoflavone isolated from Maclura pomifera fruits, against DZN-induced pulmonary toxicity. 35 male Sprague-Dawley rats were randomly allocated into five groups: Healthy, OSJ (200 mg/kg), DZN (20 mg/kg), DZN + OSJ-100, and DZN + OSJ-200. All compounds were administered orally for 28 consecutive days. Pulmonary tissues were processed for biochemical, molecular, and histopathological analyses. Quantitative analyses included biochemical and ELISA assays (n = 7 per group), as well as Western blot and qRT-PCR (n = 3 per group). DZN exposure produced lipid peroxidation (elevated MDA) accompanied by suppression of GSH and SOD activity, alongside transcriptional activation of ER stress markers (Eif2α, Atf4, Xbp1, Chop) and inflammatory mediators (Tlr4, Il10, NF-κB, TNF-α, IL-1β, iNOS, COX-2). Apoptotic balance was disrupted, with BAX and Caspase-3 elevated and BCL2 reduced. Protein data suggested that OSJ partially mitigated these cytokines, potentially showing less efficiency against IL-6 and especially mature IL-1β. Histopathology revealed alveolar disruption, leukocyte infiltration, hemorrhage, and tissue degeneration. These alterations were less pronounced in OSJ-treated groups in a dose-dependent manner, with the 200 mg/kg dose providing substantial but not complete restoration of redox homeostasis, attenuation of inflammatory and apoptotic signaling, and preservation of pulmonary architecture. These findings position OSJ as a potential candidate warranting further investigation against organophosphate-induced lung injury.
    Keywords:  Apoptosis; Diazinon; Endoplasmic Reticulum Stress; Lung injury; Osajin; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.tice.2026.103723
  9. Adv Sci (Weinh). 2026 Jun 23. e76148
    Inhibition of KDEL Receptors Remodels the Tumor Microenvironment for T Cell Independent Tumor Regression.
    Shakti P Pattanayak, Hong Wang, Belinda Willard, Timothy A Chan, William C Merrick, Zheng-Rong Lu, Boaz Tirosh.
      Tumor immunotherapy is supported by low-grade inflammatory conditions in the microenvironment, triggered by immunogenic cell death (ICD). However, ICD is dampened when tumors acquire resistance, affecting immune recognition. KDEL receptors (KDELRs), through a retrograde Golgi-to-ER transport, prevent spontaneous secretion of KDEL proteins. We report that inhibition of a single KDELR in a minor fraction of tumor cells, primarily KDELR2, provokes robust infiltration of macrophages and neutrophils into the tumor microenvironment, resulting in regression of both immunogenic and non-immunogenic tumors initially independently of T cells. Importantly, in the course of regression, anti-tumor T cells are primed, conferring protection against a second challenge. Recapitulated by intratumoral delivery of siDKELR2 utilizing lipid nanoparticles, we implicate KDELR2 as a target to unleash an unusual robust innate immune response, which represents a tractable approach to initiate an adaptive response downstream, bypassing conventional ICD-inducing therapies. We propose KDELR targeting as a strategy to improve immunotherapy across tumor types, including "cold" tumors resistant to T cell-based immunotherapies.
    Keywords:  ER stress; calreticulin; cancer immunity cycle; immunogenic cell death; innate immunity
    DOI:  https://doi.org/10.1002/advs.76148
  10. J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):
    PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
    Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.
      Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.
    DOI:  https://doi.org/10.1083/jcb.202507087
  11. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2610001123
    IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
    Dongyue Liu, Yu Li, Shuai Huang, Yufang Xu, Lei Sun, Wen Li, Cahir J O'Kane, David C Rubinsztein, Bingwei Lu, Shuangxi Li.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.
    Keywords:  IRE1; TDP-43/TARDBP; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1073/pnas.2610001123
  12. Cancers (Basel). 2026 Jun 16. pii: 1953. [Epub ahead of print]18(12):
    Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.
    Yuling Chi, Qiuying Chen, Eduardo Mere Del Aguila, Steven S Gross, John A Wagner, Shannon M Reilly, David M Nanus, Lorraine J Gudas.
      Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [13C2]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target.
    Keywords:  ATF4; clear cell renal cell carcinoma (ccRCC); glycolysis; metabolomics; mitochondrial oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cancers18121953
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒03 at 14:38.