bims-unfpre 2025-08-31 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–08–31
seven papers selected by
Susan Logue, University of Manitoba

IRE1α modulates M1 oncolytic virus sensitivity via ER stress regulation in bladder cancer.
The IRE1α/XBP1-mediated upregulation of LMTK2 attenuates endoplasmic reticulum stress by enhancing autophagic activity.
The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.
UPR deficiency leads to poor growth, aneuploidy, and a trade-off between ER and general proteostasis in yeast.
Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier.
The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer.
STK26 Promotes the Stabilization of ATF6 to Facilitate the Progression of Colorectal Cancer.

Cancer Drug Resist. 2025 ;8 41

IRE1α modulates M1 oncolytic virus sensitivity via ER stress regulation in bladder cancer.

Cheng Hu, Song Wei, Wenbo Zhu, Boran Lv, Shuhao Li, Baiyu Liu, Guangmei Yan, Ying Liu.

  Aim: Muscle-invasive bladder cancer (MIBC) remains lethal despite promising oncolytic virotherapy, hindered by tumor-intrinsic resistance. This study aimed to elucidate the molecular basis underlying differential sensitivity to the oncolytic M1 virus in bladder cancer. Methods: Bladder cancer cell lines with varying sensitivity to M1 were analyzed for endoplasmic reticulum (ER) stress responses and unfolded protein response (UPR) pathway activation. IRE1α expression was modulated using small interfering RNA and a selective inhibitor. Viral cytotoxicity, replication, and apoptosis were assessed using viability assays, immunofluorescence, electron microscopy, and immunoblotting. In vivo antitumor efficacy was assessed using xenografted mice. Clinical relevance was examined using patient-derived cells and survival data from The Cancer Genome Atlas. Results: M1 virus induced ER stress and apoptosis in sensitive cells (e.g., T24, UM-UC-3) supporting viral protein expression, whereas low-sensitivity cells like EJ showed minimal response due to limited viral replication. In moderately sensitive cells, M1 replication led to viral protein accumulation, triggering IRE1α upregulation, which in turn limited further protein buildup and apoptosis. IRE1α inhibition enhanced M1-induced ER stress, apoptotic signaling, and oncolysis without affecting viral replication capacity. In vivo, M1 plus STF083010 achieved greater tumor suppression than monotherapy without added toxicity. Analysis of patient-derived cells and TCGA data further revealed downregulation of IRE1α in primary tumors and its potential association with worse prognosis. Conclusion: IRE1α modulates M1-induced viral protein accumulation and cell death. Inhibiting IRE1α enhances ER stress and potentiates the oncolytic effect of M1 virus. Targeting IRE1α may improve M1-based virotherapy outcomes in accessible tumors.

Keywords:  ER stress; IRE1α; Oncolytic M1 virus; UPR; bladder cancer

DOI:  https://doi.org/10.20517/cdr.2025.119
Cancer Lett. 2025 Aug 18. pii: S0304-3835(25)00563-4. [Epub ahead of print]633 217993

The IRE1α/XBP1-mediated upregulation of LMTK2 attenuates endoplasmic reticulum stress by enhancing autophagic activity.

Jie Lun, Xiuxiu Li, Rongjing Zhang, Chenyao Wang, Yanqing Qin, Yu Li, Zhiqiang Ling, Mengchao Yu, Jing Fang.

  Lemur tyrosine kinase 2 (LMTK2), a transmembrane protein, is not well characterized regarding its biological functions and regulatory mechanisms. Herein, we demonstrate that LMTK2 functions as an ER stress-induced protein that plays a crucial role in regulating ER stress and safeguarding cells through autophagy pathway. Our study reveals that ER stressors thapsigargin (Tg) and tunicamycin (Tm) upregulate LMTK2 expression via IRE1α-XBP1s signaling in colon cancer cells. LMTK2 overexpression ameliorates Tm-induced ER stress, whereas its knockdown did the opposite. LMTK2 depletion impairs Tg-induced autophagy. The protective effect of LMTK2 against ER stress is autophagy-dependent, evidenced by LMTK2's inability to mitigate ER stress when autophagy was pharmacologically inhibited. These findings establish that LMTK2-mediated ER stress alleviation is dependent on its facilitation of autophagic processes. Importantly, LMTK2 demonstrates a protective role against ER stress-induced apoptosis that is abolished upon autophagy inhibition. Xenograft experiments reveal that LMTK2-deficient tumors exhibited increased apoptotic cells, elevated GRP78 expression, and reduced LC3 levels. Analyses of clinical colon cancer specimens indicate that LMTK2 expression levels correlate with tumor grades and poor patients' survival. These results provide compelling evidence that LMTK2 functions as an ER stress-responsive protein that maintains ER homeostasis and promotes cell survival via autophagy-dependent mechanisms.

Keywords:  Autophagy; Cancer; ER stress; Lemur tyrosine kinase 2

DOI:  https://doi.org/10.1016/j.canlet.2025.217993
Cell Commun Signal. 2025 Aug 20. 23(1): 374

The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.

Jiayi E Wang, Charanya Muralidharan, Armando A Puente, Titli Nargis, Jacob R Enriquez, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey.

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Macrophages infiltrate islets early in T1D pathogenesis, preceding the influx of T- and B-lymphocytes. The integrated stress response (ISR), a cellular pathway activated during stress, coordinates adaptive changes in gene expression to maintain cell function and survival. To study the ISR in macrophages, bone-marrow-derived macrophages were treated with a pharmacological inhibitor of the ISR (ISRIB) and polarized to a proinflammatory M1-like state. We observed a reduction in the number of proinflammatory macrophages, as well as a decrease in iNOS mRNA and protein levels, following ISRIB treatment. RNA-sequencing revealed a reduction in pathways related to stress responses, including ER stress, reactive oxygen species (ROS) regulation, and autophagy, as well as migration pathway genes. ISRIB treatment led to decreased macrophage migration after stimulation in vitro and reduced migration of macrophages to the site of injury after tailfin injury in zebrafish in vivo. Interestingly, ISRIB mediated reduction of M1-like macrophages and reduction of migration was recapitulated by the inhibition of PKR but not PERK, both upstream ISR kinases, highlighting PKR as a key mediator of the ISR in macrophages. Pre-diabetic female non-obese diabetic (NOD) mice administered ISRIB demonstrated an overall reduction in the macrophage numbers in the pancreatic islets. Additionally, the insulitic area of pancreata from ISRIB treated NOD mice had increased PD-L1 levels. PD-L1 protein but not mRNA levels were increased in M1-like macrophages after ISR and PKR inhibition. Our findings identify the ISR, particularly via PKR, as a critical regulator of macrophage driven inflammation and migration in T1D. Our study offers new insights into ISR signaling in macrophages, demonstrating that the ISR may serve as a potential target for intervention in macrophages during early T1D pathogenesis.

Keywords:  Diabetes; Inflammation; Integrated stress response (ISR); Macrophages; Migration; Pancreatic islet; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1186/s12964-025-02372-z
Genes Dev. 2025 Aug 22.

UPR deficiency leads to poor growth, aneuploidy, and a trade-off between ER and general proteostasis in yeast.

Constantine Bartolutti, Allison J Kim, Yanzhe Ma, Thiago P Fernandes, Charles Boone, Marko Jovanovic, Gloria A Brar.

  The unfolded protein response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to endoplasmic reticulum (ER) stressors. Although the UPR is not thought to be necessary for cellular fitness of wild-type cells in the absence of stress, we found that UPR deficiency led to poor growth in cycling mitotic yeast cells. This led to pervasive adaptive aneuploidy of specific chromosomes that was seen in divergent strain backgrounds, indicating an important basal role for this pathway that was missed by studies of the most common laboratory-derived strains. Aneuploid UPR-deficient cells grew better than euploid UPR-deficient cells but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes could phenocopy the effects of aneuploidy, indicating that the reason UPR-deficient cells become aneuploid is to counteract protein folding stress in the ER. Proteomic analyses indicate that expression of a small subset of stress-induced UPR targets is supported by basal UPR activity, including the chaperone Kar2/BiP. Together, our results reveal an unexpected role for the UPR in baseline ER folding that is important enough to safeguard cellular fitness that cells tolerate the substantial proteostatic costs that result from aneuploidy to counteract its loss.

Keywords:  UPR; aneuploidy; yeast

DOI:  https://doi.org/10.1101/gad.352490.124
Immunity. 2025 Aug 22. pii: S1074-7613(25)00332-2. [Epub ahead of print]

Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier.

Göksu Gökberk Kaya, Robin Schwarzer, Marius Dannappel, Katerina Vlantis, Ulrike Göbel, Vangelis Kondylis, Sergei A Nedospasov, Manolis Pasparakis.

  Endoplasmic reticulum (ER) stress and necroptosis are associated with the pathogenesis of inflammatory bowel disease (IBD); however, the potential crosstalk between these pathways is unclear. Here, we show that intestinal epithelial cell (IEC)-specific X-box binding protein 1 (XBP1) deficiency strongly aggravates the development of necroptosis-induced colitis, but not ileitis, in mice lacking caspase-8 or its adapter Fas associated with death domain (FADD) in IECs. Mechanistically, XBP1 ablation led to diminished mucin 2 (MUC2) expression and impaired mucus layer formation in the colon, which allowed bacteria to penetrate and reach the epithelial surface. This was not sufficient to trigger colitis in the presence of an intact epithelial monolayer but synergized with IEC necroptosis to induce severe colon inflammation. Our results revealed that XBP1 and caspase-8 control different components of the intestinal barrier that synergize to maintain mucosal immune homeostasis and prevent colon inflammation. This could be relevant for the better understanding of the mechanisms causing IBD.

Keywords:  FADD; IRE1; XBP1; caspase-8; impaired mucus layer; inflammatory bowel disease; intestinal epithelial barrier; mucin 2; necroptosis; unfolded protein response

DOI:  https://doi.org/10.1016/j.immuni.2025.07.023
Cancer Cell Int. 2025 Aug 21. 25(1): 310

The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer.

Yehao Guo, Juyong Liang, Lingling Ding, Jiajun Wu, Weidong Teng, Jiafeng Wang, Liehao Jiang, Zhuo Tan.

   BACKGROUND: Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood.
METHODS: Methods: To investigate the anticancer activity of lenvatinib and anlotinib in vivo, a subcutaneous tumor model was established in mice. The pharmacological effects of these agents on ATC cells were assessed using various assays, including CCK-8, colony formation, transwell, and sphere-forming assays. Angiogenesis was evaluated using a tubule formation assay. Reactive oxygen species (ROS) levels were measured by flow cytometry, and levels of ferroptosis and endoplasmic reticulum (ER) stress were determined through western blot assays. Immunohistochemistry analyses were used to profile the expression of GPX4, HO-1, PERK, and CHOP in tumor tissues.
RESULTS: Both lenvatinib and anlotinib demonstrated dose- and time-dependent inhibition of Luciferase-8505 C-induced subcutaneous tumors in mice, with anlotinib showing greater efficacy than lenvatinib. In vitro experiments revealed that while both drugs were effective at inhibiting angiogenesis, anlotinib displayed superior antitumor effects in terms of cell viability, proliferation, tumor sphere formation, migration, and invasion. Mechanistic studies indicated that anlotinib induced ROS-mediated ferroptosis through the ER stress pathway, a response not observed with lenvatinib treatment.
CONCLUSION: Anlotinib showed superior efficacy in treating ATC compared to lenvatinib, independent of their anti-angiogenic properties. The ability of anlotinib to induce ER stress-mediated ferroptosis suggests that targeting ferroptosis may hold promise as a therapeutic strategy for ATC.

Keywords:  Anaplastic thyroid cancer; Anlotinib; Endoplasmic reticulum stress; Ferroptosis; Lenvatinib; Signal pathways.

DOI:  https://doi.org/10.1186/s12935-025-03947-z
Int J Mol Sci. 2025 Aug 20. pii: 8052. [Epub ahead of print]26(16):

STK26 Promotes the Stabilization of ATF6 to Facilitate the Progression of Colorectal Cancer.

Yuetian Ding, Jianwei Ren, Changwei Hu, Jiayue Han, Jin Zhang, Zhengsha Huang, Youfan Zhang, Weizhou Wang, Weizhe Yu, Qipeng Shu, Shangze Li.

  STK26 is highly expressed in colorectal cancer (CRC) and linked to tumorigenesis. Although implicated in unfolded protein response (UPR)-related oxidative stress, whether STK26 regulates CRC occurrence via the ATF6 pathway-a classic UPR branch governing proteostasis and cell survival-remains unestablished. In our research, we found that STK26 expression aberrantly upregulated in CRC is closely associated with poor prognosis. In vitro, tumor phenotype assays showed that STK26 drives CRC cell growth, proliferation, and migration. These effects were reversed by the ATF6 inhibitor Ceapin-A7, demonstrating that STK26's oncogenic function depends on ATF6. Moreover, transcriptome sequencing revealed that STK26 is associated with the protein folding, sorting, and degradation pathway, and a luciferase reporter assay showed that STK26 activated the ATF6 signal pathway. Furthermore STK26 interacted with p50ATF6 and enhanced its protein stabilization. In vivo studies demonstrated that the administration of the STK26 inhibitor Hesperadin significantly suppressed CRC growth, suggesting a tumor-promoting role for STK26 in CRC pathogenesis. In summary, our research reveals that STK26 is a novel regulator that promotes the growth, proliferation, and migration of CRC cells by activating the ATF6 signaling pathway and stabilizing p50ATF6. Hence, the STK26-ATF6 axis has the potential to become a new target for treating colorectal cancer.

Keywords:  ATF6; CRC; STK26; UPR; tumorigenesis

DOI:  https://doi.org/10.3390/ijms26168052