bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–10–04
seven papers selected by
Susan Logue, University of Manitoba
  1. Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.
  2. Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.
  3. RABC1 regulates ER-phagy to maintain er homeostasis in plants.
  4. Tracking cellular biomolecular condensate dynamics under proteostatic stress with middle-down phosphoproteomics.
  5. Histone H4 lysine 20 tri-methylation safeguards breast cancer lineage fidelity and unfolded protein response.
  6. The inflammatory UPR-IFNG axis reveals LBP as a survival and immunotherapy-response marker in hepatocellular carcinoma.
  7. ER stress-associated apoptosis and pyroptosis-like changes in Kikuchi-Fujimoto disease.
  1. Cell Death Dis. 2026 Aug 01. pii: 840. [Epub ahead of print]17(1):
    Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.
    Maj Sofie Ørum-Madsen, Jessica Pihl, Thomas M Clausen, Charlotte Spliid, Anne-Chloé Dhez, Hai-Feng Zhang, Yen-Hsi Chen, Elena Ethel Vidal-Calvo, Tobias Gustavsson, Michael Lizardo, Irina Nelepcu, Joey Lo, Jeffrey D Esko, Htoo Zarni Oo, Alberto Delaidelli, Mette Ørskov Agerbæk, Anne Steinø, Nader Al Nakouzi, Ali Salanti, Poul Sorensen, Mads Daugaard.
      Tumors must adapt to high levels of endoplasmic reticulum (ER) stress to sustain tumor growth and metastases. The chaperone GRP78 (BiP/HSPA5) is a key component of the unfolded protein response (UPR) and essential for ER stress management and adaptive signaling supporting pro-survival UPR activities. Here, we report that oncofetal chondroitin sulfate (CS) glycosaminoglycans are required for ER stress adaptation in osteosarcoma. When osteosarcoma cells encounter ER stress, they upregulate 4-O-sulfated CS at the expense of other glycosaminoglycans leading to a reconfiguration of the glycocalyx in favor of an oncofetal CS subtype. Genetic ablation of the CS synthesis pathway impairs the UPR by preventing osteosarcoma cells from mounting GRP78 expression in response to ER stress. CS deficiency makes osteosarcoma cells hypersensitive to inhibition of GRP78 under both ambient and ER stress conditions, and acute ER stress drives CS-defective osteosarcoma cells into an apoptotic cell death that can be rescued by re-instating CS 4-O-sulfation capacity. This has direct implications for the metastatic progression of osteosarcoma, whereby oncofetal CS protects dissociated osteosarcoma cells from anoikis to allow pulmonary colonization in mice. Our data identify CS glycosaminoglycans as a critical component of the UPR that permits osteosarcoma cells to manage ER stress.
    DOI:  https://doi.org/10.1038/s41419-026-09151-9
  2. Front Nutr. 2026 ;13 1915419
    Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.
    Merve Seylan, Sule Arslan, Halit Tanju Besler.
      Inflammatory bowel diseases (IBD) are chronic inflammatory disorders that arise from the complex interplay among genetic predisposition, immune dysregulation, environmental factors, and disruption of intestinal epithelial barrier integrity. Increasing evidence suggests that endoplasmic reticulum (ER) stress may represent an important mechanistic pathway in this multifactorial pathogenesis. Experimental evidence indicates that dietary patterns and nutrient-derived factors may modulate ER stress responses. In this review, the role of ER stress in IBD is discussed from a mechanistic perspective, with particular emphasis on the effects of nutrition on ER stress pathways and the relationship between these interactions and IBD pathogenesis. The available findings are evaluated according to whether they derive from direct human IBD studies, experimental colitis models, intestinal cellular systems, or indirect non-intestinal models. Evidence derived predominantly from experimental and non-intestinal metabolic models indicates that high-fat and high-fructose exposures can activate PERK- and IRE1-associated signaling and CHOP-related terminal responses; however, their direct effects on intestinal UPR signaling and epithelial barrier integrity in human IBD have not been established. In contrast, polyunsaturated fatty acids, flavonoids, polyphenols, and certain micronutrients have been reported to modulate selected UPR markers and support cellular adaptation in experimental systems, although differences in dose, bioavailability, and study model limit clinical extrapolation. Collectively, current evidence suggests that ER stress may represent an important mechanistic pathway linking nutrition and intestinal inflammation, although direct causal evidence linking nutritional exposures to mucosal ER stress and clinical outcomes in humans remains limited. Controlled dietary studies incorporating standardized, pathway-specific mucosal biomarkers are required before this mechanistic framework can inform personalized nutritional strategies or ER-stress-targeted interventions.
    Keywords:  endoplasmic reticulum stress; inflammation; inflammatory bowel disease; nutrition; unfolded protein response
    DOI:  https://doi.org/10.3389/fnut.2026.1915419
  3. Autophagy. 2026 Sep 28.
    RABC1 regulates ER-phagy to maintain er homeostasis in plants.
    Shuai Hu, Xiaohui Ma, Zhengjia Wang, Jinbo Shen.
      Endoplasmic reticulum (ER)-phagy is an important ER quality-control pathway that selectively removes misfolded or unfolded proteins and damaged ER membranes through autophagic degradation in the vacuole. Recent studies have identified small guanosine triphosphatases (GTPases) as important regulators of the autophagy pathway. However, how they couple stress signals to ER-phagy remains poorly understood in plants. Our recent work demonstrated that RABC1 regulates ER-phagy under dithiothreitol (DTT)-, tunicamycin (TM)-, and heat-induced ER stress through interaction with the exocyst complex component SEC5A. Upon ER stress, green fluorescent protein (GFP)-RABC1 was recruited to the ATG8e-positive autophagosomes from the ER and Golgi in root cells, whereas autophagic flux and calnexin 1 (CNX1)-mRFP-tagged ER membranes turnover were impaired in the rabc1 mutant. Together, our findings support a model in which RABC1 acts as a molecular switch that interacts with distinct effectors to regulate autophagy under different stress conditions.
    Keywords:  Autophagy; Er-phagy; RABC1; SEC5A; er stress
    DOI:  https://doi.org/10.1080/15548627.2026.2739788
  4. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753649. [Epub ahead of print]
    Tracking cellular biomolecular condensate dynamics under proteostatic stress with middle-down phosphoproteomics.
    Boomathi Pandi, Dominic C M Ng, Peyton Schaal, Lorena Alamillo, Shaonil Binti, Edward Lau, Maggie P Y Lam.
      Coordination of biological function requires the partition of cellular components including into biomolecular condensates, but an overall landscape of how protein compartmentalize into higher-order assemblies under stress is still emerging. We apply proteome-wide solubility profiling to compare the compositions of NP-40-insoluble proteins and their phosphorylation status, using a new mass spectrometry-based hybrid bottom-up and chemical middle-down proteomics approach to analyze the solubility behavior of 8,740 proteins and 31,647 phosphopeptides under normal and ER stress conditions. Cell stress induces a pervasive differential partition of proteins in and out of detergent- insoluble cellular compartments. This differential partition is partially orthogonal to stress-induced abundance changes and comprises both phosphorylation-dependent and phosphorylation-independent mechanisms. Whereas phosphorylation-independent partition changes involve largely secretory pathway proteins and implicate higher-order assemblies of chaperones and clients, phosphorylation-based partitions suggest a dynamic rearrangement of biomolecular condensate compositions across cytoplasmic and nuclear ribonucleoprotein assemblies. The accumulation of serine/arginine rich (SR) proteins and other annotated nuclear speckle members in the condensate-rich proteome fractions emerges as a central feature of stress-induced remodeling. Our results establish global solubility dynamics as an integral component of proteome stress response and implicates broad involvements of splice factor spatial reorganization as a prominent facet of ER stress response.
    DOI:  https://doi.org/10.64898/2026.09.22.753649
  5. Nat Commun. 2026 Aug 22. pii: 10258. [Epub ahead of print]17(1):
    Histone H4 lysine 20 tri-methylation safeguards breast cancer lineage fidelity and unfolded protein response.
    Zheqi Li, Amatullah Tawawalla, Pierre Foidart, Marco Seehawer, Jun Nishida, Ernesto Rojas Jimenez, Triet M Bui, Xiao-Yun Huang, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Laura E Stevens, Miguel Munoz Gomez, Rong Li, Henry W Long, Kornelia Polyak.
      Triple-negative breast cancer (TNBC) has poor outcomes and few effective treatments, partly because of epigenetic heterogeneity. We show that the heterochromatin mark H4K20me3 is more variable than H3K9me3 across normal and malignant breast tissues, and that H4K20me3-enriched regions are linked to more open chromatin and active transcription. Pharmacologic inhibition of the H4K20me3 methyltransferases KMT5B and KMT5C with A-196 decreases H4K20me3 and increases H4K20me1 at loci involved in lineage identity, stress responses, and the cell cycle. A-196 suppresses tumor growth in vivo while promoting mesenchymal features and the unfolded protein response (UPR). Multi-omic profiling shows that mesenchymal TNBCs have the lowest H4K20me3 levels and the greatest sensitivity to UPR stress. In basal TNBC, KMT5B&5 C inhibition drives mesenchymal transition and elevated endoplasmic reticulum stress-associated growth arrest via E2F4. Combining A-196 with the HSP90, IRAK4 inhibitors, or STING agonist synergistically reduces TNBC tumor growth. These findings nominate KMT5B&5C as promising therapeutic targets in TNBC.
    DOI:  https://doi.org/10.1038/s41467-026-76773-0
  6. Transl Oncol. 2026 Sep 28. pii: S1936-5233(26)00375-X. [Epub ahead of print]73 103039
    The inflammatory UPR-IFNG axis reveals LBP as a survival and immunotherapy-response marker in hepatocellular carcinoma.
    Nan Luo, Yu Tian.
       BACKGROUND: Liver hepatocellular carcinoma (LIHC) remains difficult to stratify because tumor heterogeneity and an immunosuppressive microenvironment limit immune checkpoint blockade (ICB). The unfolded protein response (UPR) and interferon-gamma (IFNG) signaling connect cellular stress with tumor inflammation, but clinically interpretable biomarkers linking these programs to prognosis and treatment response remain limited.
    METHODS: We integrated 278,337 cells from three single-cell RNA sequencing (scRNA-seq) datasets with bulk transcriptomic cohorts. Malignant-cell programs were mapped at single-cell resolution. Weighted gene co-expression network analysis (WGCNA) identified IFNG-associated modules, and ConsensusClusterPlus defined UPR-related patient clusters. Random Survival Forest and CoxBoost were then used to select prognostic genes.
    RESULTS: Lipopolysaccharide-binding protein (LBP) emerged as the top-ranked prognostic marker for LIHC. In GSE116174, GSE144269, and GSE14520, high LBP expression was associated with poorer overall survival. LBP also correlated with immune-cell infiltration, tumor microenvironment scores, immune modulators, and ICB-response determinants. Across public immunotherapy datasets, LBP showed response-classification value. In vitro, LBP knockdown reduced LIHC cell proliferation.
    CONCLUSIONS: This study identifies LBP as a UPR-related and IFNG-associated candidate biomarker for LIHC prognosis and immunotherapy-response stratification. These findings support further preclinical and clinical validation of LBP in liver cancer.
    Keywords:  Hepatocellular carcinoma; IFNG; Inflammation; LBP; UPR
    DOI:  https://doi.org/10.1016/j.tranon.2026.103039
  7. J Clin Exp Hematop. 2026 ;66(3): 272-275
    ER stress-associated apoptosis and pyroptosis-like changes in Kikuchi-Fujimoto disease.
    Shigeyuki Asano, Koji Shikano, Kazuki Yamazaki, Yoichiro Sogame, Rin Yamada, Yuko Hashimoto, Yasuhiro Nakamura, Yoshihiro Komohara.
      
    Keywords:  Kikuchi–Fujimoto disease; endoplasmic reticulum stress; gasdermin D; pyroptosis
    DOI:  https://doi.org/10.3960/jslrt.26037
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