bims-unfpre 2025-01-19 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–01–19
six papers selected by
Susan Logue, University of Manitoba

MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2.
IRE1 is a Promising Therapeutic Target in Pancreatic Cancer.
Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation.
E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.
Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer.
Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Mol Cell Biochem. 2025 Jan 13.

MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2.

Siyuan Peng, Yan Zhao, Wang Jiang, Yan Long, Tian Hu, Mengling Li, Jinyue Hu, Yueming Shen.

  Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.

Keywords:  Endoplasmic reticulum stress; Inflammatory bowel disease; MAPK; NOD2

DOI:  https://doi.org/10.1007/s11010-025-05212-3
Am J Physiol Cell Physiol. 2025 Jan 16.

IRE1 is a Promising Therapeutic Target in Pancreatic Cancer.

Denise Lucas, Tamal Sarkar, Clara Y Niemeyer, Julian C Harnoss, Martin Schneider, Moritz J Strowitzki, Jonathan M Harnoss.

  Pancreatic cancer (PC) is one of the most aggressive malignancies, characterized by an increasing incidence and unfavorable prognosis. Despite recent advances, surgical resection combined with chemotherapy remains the only potentially curative therapeutic option. Therefore, it is of paramount importance to identify novel therapeutic targets and develop effective treatment strategies. Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of PC, originates from exocrine cells and is subjected to both intrinsic and extrinsic cellular stresses, including oncogene activation, loss of tumor suppressors, a hypoxic and immunosuppressive tumor microenvironment (TME), and chemotherapy, causing an accumulation of misfolded proteins within the endoplasmic reticulum (ER). The loss of ER proteostasis activates the unfolded protein response (UPR), an intracellular sensing-signaling network that enables cancer cells to alleviate ER stress and restore cellular proteostasis. The key UPR sensor Inositol-Requiring Enzyme 1 (IRE1) is an ER membrane protein that activates the transcription factor X-Box Protein 1 Spliced (XBP1s) through its cytoplasmic kinase-RNase module, promoting protein folding, secretion capacity, and proteasomal degradation of misfolded proteins. Additionally, it regulates IRE1-dependent decay (RIDD) of various mRNA and functions through scaffold interactions. In this review, we synthesize current evidence on the cell-autonomous and cell-non-autonomous roles of IRE1 in tumor initiation, progression, metastasis, and drug resistance in PDAC and outline key research directions to investigate IRE1 as a potential therapeutic target.

Keywords:  IRE1; PDAC; endoplasmic reticulum stress; pancreatic cancer; unfolded protein response

DOI:  https://doi.org/10.1152/ajpcell.00551.2024
Cell Death Differ. 2025 Jan 11.

Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation.

Xiaolu Wang, Qianqian Wang, Hong Wang, Guodi Cai, Yana An, Peiqing Liu, Huihao Zhou, Hong-Wu Chen, Shufeng Ji, Jiantao Ye, Junjian Wang.

Clinical treatment options for triple-negative breast cancer (TNBC) are currently limited to chemotherapy because of a lack of effective therapeutic targets. Recent evidence suggests that long noncoding RNAs (lncRNAs) encode bioactive peptides or proteins, thereby playing noncanonical yet significant roles in regulating cellular processes. However, the potential of lncRNA-translated products in cancer progression remains largely unknown. In this study, we identified a previously undocumented small protein encoded by the lncRNA LINC02870. This protein is localized at the endoplasmic reticulum (ER) and participates in ER stress, thus, we named it the endoplasmic reticulum stress protein (ERSP). ERSP was highly expressed in TNBC tissues, and elevated LINC02870 content was correlated with poor prognosis in TNBC patients. Loss of ERSP inhibited TNBC growth and metastasis both in vitro and in vivo. The pro-oncogenic effects of ERSP could be attributed to its selective activation of the IRE1α/XBP1s branch. ERSP enhances the unfolded protein response (UPR) by interacting with XBP1s, facilitating the nuclear accumulation of XBP1s, thereby promoting the expression of ER stress-related genes. These findings highlight the regulatory role of the lncRNA-encoded protein ERSP in ER stress and suggest that it is a potential therapeutic target for TNBC.

DOI: https://doi.org/10.1038/s41418-025-01443-5
Genes Dev. 2024 Dec 30.

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.

Alexis U Oguh, Matthew W Haemmerle, Sabyasachi Sen, Andrea V Rozo, Shristi Shrestha, Jean-Philippe Cartailler, Hossein Fazelinia, Hua Ding, Sam Preza, Juxiang Yang, Xiaodun Yang, Lori Sussel, Juan R Alvarez-Dominguez, Nicolai Doliba, Lynn A Spruce, Rafael Arrojo E Drigo, Doris A Stoffers.

  The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain (Spop βKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.

Keywords:  diabetes; proteasome; ubiquitin; unfolded protein response; β cells

DOI:  https://doi.org/10.1101/gad.352010.124
Neoplasia. 2025 Jan 15. pii: S1476-5586(24)00156-8. [Epub ahead of print]60 101115

Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer.

Georgia Porter, Murray D Norris, Minoti Apte, Angelica M Merlot.

   INTRODUCTION: The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples.
METHODS: Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software.
RESULTS: BiP and CHOP were upregulated in CAFs and endothelial cells in PDAC sections relative to non-neoplastic pancreas sections. High BiP expression in CAFs and endothelial cells was associated with greater vascular invasion and in immune cells was correlated with increased tumor size. High CHOP expression in immune cells correlated with poor patient survival. CAFs and immune cells were more likely to express BiP or CHOP when located close (< 20 μm) to tumor cells. High expression of CHOP in CAFs close to tumor cells correlated with improved patient survival.
CONCLUSION: For the first time, this study demonstrated that ER stress occurs in CAFs and immune cells predominantly in proximity to tumor cells in PDAC patient tissue. The correlation of high ER stress in immune cells with poor patient survival highlights the importance of the TME and the use of spatial analysis for the identification of novel biomarkers.

Keywords:  Cancer associated fibroblasts; Endoplasmic reticulum stress; Pancreatic cancer; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.neo.2024.101115
Life Sci Alliance. 2025 Mar;pii: e202302259. [Epub ahead of print]8(3):

Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.

DOI: https://doi.org/10.26508/lsa.202302259