bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–03–16
six papers selected by
Susan Logue, University of Manitoba
  1. Endoplasmic Reticulum Stress: Implications in Diseases.
  2. XBP1: A key regulator in breast cancer development and treatment.
  3. Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.
  4. Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.
  5. Suppression of stress granule formation is a vulnerability imposed by mutant p53.
  6. Induction of MASH-like pathogenesis in the Nwd1-/- mouse liver.
  1. Protein J. 2025 Mar 13.
    Endoplasmic Reticulum Stress: Implications in Diseases.
    Neha Sylvia Walter, Varun Gorki, Rishi Bhardwaj, Pradeep Punnakkal.
      Endoplasmic reticulum (ER) is a specialized organelle that plays a significant role in cellular function. The major functions of ER include protein synthesis and transport, folding of proteins, biosynthesis of lipids, calcium (Ca2+) storage, and redox balance. The loss of ER integrity results in the induction of ER stress within the cell due to the accumulation of unfolded, improperly folded proteins or changes in Ca2+ metabolism and redox balance of organelle. This ER stress commences the Unfolded Protein Response (UPR) that serves to counteract the ER stress via three sensors inositol requiring protein-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor-6 (ATF6) that serve to establish ER homeostasis and alleviates ER stress. Severe ER dysfunction ultimately results in the induction of apoptosis. Increasing shreds of evidence suggest the implication of ER stress in the development and progression of several diseases viz. tuberculosis, malaria, Alzheimer's disease, Parkinson's disease, diabetes, and cancer. Activation of ER stress can be beneficial for treating some diseases while inhibiting the process can be useful in others. A deeper understanding of these pathways can provide key insights in designing novel therapeutics to treat these diseases.
    Keywords:  Cancer; Diseases; ER Stress; Endoplasmic reticulum; Unfolded Protein Response
    DOI:  https://doi.org/10.1007/s10930-025-10264-x
  2. Pathol Res Pract. 2025 Mar 04. pii: S0344-0338(25)00092-5. [Epub ahead of print]269 155900
    XBP1: A key regulator in breast cancer development and treatment.
    Ya-Ya Wang, Sheng-Kai Geng, Yi-Peng Fu, Jian Sun.
      X-box binding protein 1 (XBP1), as a transcription factor, plays pivotal role in unfolded protein response (UPR), which is activated in response to endoplasmic reticulum (ER) stress to restore ER homeostasis. IRE1α/XBP1 pathway is a key component of UPR, and the expression levels of XBP1 can dictate the fate of cells under ER stress, either promoting survival or driving apoptosis. High expression of XBP1 in breast tumors is closely associated with poor prognosis. The paper elucidates the biological functions of XBP1 and its involvement in UPR, while also surveying the latest research on how XBP1 influences immunity, metabolism, apoptosis, angiogenesis, and the invasive and migratory behaviors of breast cancer cells. Moreover, it contemplates the potential of XBP1 as a therapeutic target for breast cancer treatment.
    Keywords:  Breast cancer; Endoplasmic reticulum stress; Unfolded protein response; XBP1
    DOI:  https://doi.org/10.1016/j.prp.2025.155900
  3. Cancer Lett. 2025 Mar 05. pii: S0304-3835(25)00177-6. [Epub ahead of print]617 217613
    Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.
    Si Lu, Qimin Zhou, Rongjie Zhao, Lei Xie, Wen-Ming Cao, Yu-Xiong Feng.
      Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.
    Keywords:  Immunotherapy resistance; Tumor microenvironment; UPR
    DOI:  https://doi.org/10.1016/j.canlet.2025.217613
  4. Isr J Chem. 2024 Dec;pii: e202300162. [Epub ahead of print]64(12):
    Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.
    Kenny Chen, Matthew D Shoulders.
      The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm-defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N- and O-glycans installed on ER client proteins. This crosstalk between the UPR's response to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1-XBP1s arm of the UPR, may be a central regulator of protein glycosylation with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.
    Keywords:  Endoplasmic reticulum stress; N-Glycosylation; O-Glycosylation; Protein folding; Proteostasis
    DOI:  https://doi.org/10.1002/ijch.202300162
  5. Nat Commun. 2025 Mar 10. 16(1): 2365
    Suppression of stress granule formation is a vulnerability imposed by mutant p53.
    Elizabeth Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan A Dixon, Sugako Oka, Tomoo Iwakuma.
      Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.
    DOI:  https://doi.org/10.1038/s41467-025-57539-6
  6. Commun Biol. 2025 Mar 11. 8(1): 348
    Induction of MASH-like pathogenesis in the Nwd1-/- mouse liver.
    Seiya Yamada, Hayato Ogawa, Miona Funato, Misaki Kato, Kazuhiko Nakadate, Tomoya Mizukoshi, Kiyoharu Kawakami, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Shin-Ichi Sakakibara.
      Endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and it's perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of Ca2+ transport from the cytosol to ER, is associated with the induction of ER stress and lipid droplet formation. We previously identified NACHT and WD repeat domain-containing protein 1 (Nwd1) localized at the ER and mitochondria. However, the physiological significance of Nwd1 outside the brain remains unclear. In this study, we revealed that Nwd1-/- mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. Nwd1-/- livers exhibited reduced SERCA2 ATPase activity and a smaller Ca2+ pool in the ER, leading to an exacerbated state of ER stress. These findings highlight the importance of SERCA2 activity mediated by Nwd1 in the pathogenesis of MASH.
    DOI:  https://doi.org/10.1038/s42003-025-07717-5
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