bims-unfpre 2025-11-16 papers

Issue of 2025–11–16
eight papers selected by
Susan Logue, University of Manitoba

Cancers (Basel). 2025 Oct 31. pii: 3534. [Epub ahead of print]17(21):

ER Stress Is Associated with a "Mesenchymal Drift" in an Anaplastic Thyroid Carcinoma Cell Line.

Dario Domenico Lofrumento, Alessandro Miraglia, Antonella Sonia Treglia, Francesco De Nuccio, Giuseppe Nicolardi, Corrado Garbi, Bruno Di Jeso.

Background/Objectives: The tumor microenvironment (TME) plays a crucial role in the progression of the malignant phenotype through several mechanisms, such as hypoxia and nutrient deprivation, among others. These insults activate several intracellular pathways, and among them are ER stress and the unfolded protein response (UPR). Our aim was to assess if a specific ER stress inducer causes an exacerbation of the malignant phenotype of anaplastic thyroid carcinoma (ATC) cells. Methods: We used an ATC cell line, FRO cells, that had not undergone a full Epithelial-Mesenchymal Transition (EMT) and an ER stress-adapted cell line derived from FRO cells, A400 cells. Western blot, immunofluorescence, scratch, and invasion assays were used to evaluate the response of the FRO and A400 cells to ER stress. Results: The FRO cells were subjected to high-level ER stress caused by 400 ng/mL of tunicamycin (Tn). This caused the death of a large fraction of cells, but eventually a population emerged that we called A400 cells. Following an over challenge with Tn, the adapted population showed suppression of the UPR, apoptosis, and stress kinase activation. Moreover, the adapted population showed an exacerbation of mesenchymal features with a more invasive phenotype. At the level of a single cell, the adapted cells, caught in the act of moving, showed high-level expressions of vimentin (VIM), fibronectin (FN), and N-cadherin. Conclusions: High-level ER stress acts as a selection factor favoring the emergence of a cell population showing "mesenchymal drift" with a more malignant phenotype.

Keywords: anaplastic thyroid carcinoma; cancer progression; endoplasmic reticulum stress

DOI: https://doi.org/10.3390/cancers17213534

Front Immunol. 2025 ;16 1694102

Endoplasmic reticulum stress and unfolded protein response in immune cell function.

Goshi Matsushima, Yuhki Yanase, Tadashi Nakagawa, Mitsuhiro Goda, Koichiro Ozawa, Toru Hosoi.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as central regulators of immune cell function and inflammatory processes. The UPR, mediated by three principal ER-resident sensors, IRE1α, PERK and ATF6, maintains cellular homeostasis under stress conditions but also contributes to pathogenesis when dysregulated. Recent studies revealed that the UPR plays critical roles not only in protein folding but also in directing immune cell fate, activation, and cytokine production. Although significant advances have been made, various questions remain regarding the cell-type-specific and context-dependent functions of ER stress responses. Understanding these mechanisms would be crucial for developing targeted therapies. Therefore, in this review, we provide a comprehensive overview of how ER stress and the UPR influence various immune cell types, including monocytes, macrophages, dendritic cells, granulocytes, T cells, B cells, microglia, and astrocytes, within both peripheral and central immune systems.

Keywords: ATF6 (activating transcription factor 6); IRE1 (inositol-requiring enzyme 1); PERK (PKR-like endoplasmic reticulum kinase); endoplasmic reticulum stress; immune cells; unfolded protein response

DOI: https://doi.org/10.3389/fimmu.2025.1694102

Int J Med Sci. 2025 ;22(16): 4561-4585

Endoplasmic Reticulum Stress in Cancer Progression: A Comprehensive Review of Its Role and Mechanisms.

Xin Yu, Wenge Li, Shengrong Sun, Juanjuan Li.

Endoplasmic reticulum (ER) stress plays a pivotal role in tumor progression. As research in tumor biology advances, the relationship between ER stress and tumor initiation, development, and immune regulation has increasingly attracted attention. ER stress activates the unfolded protein response (UPR), thereby affecting key processes in tumor cells, including metabolism, proliferation, invasion, metastasis, and drug resistance. Moreover, it modulates tumor immune responses by regulating the functions of immune cells within the tumor microenvironment. This review consolidates the concept of ER stress as a central signaling hub that dictates cell fate and extensively remodels the tumor ecosystem. From a clinical perspective, this understanding provides a strong rationale for therapeutically targeting the UPR, suggesting that combining ER stress modulators with immunotherapy represents a promising strategy to overcome therapeutic resistance and improve patient outcomes.

Keywords: cancer; endoplasmic reticulum stress; tumor microenvironment; unfolded protein response

DOI: https://doi.org/10.7150/ijms.120874

Nucleic Acids Res. 2025 Oct 28. pii: gkaf1072. [Epub ahead of print]53(20):

Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response.

Lorenzo Lafranchi, Glancis Luzeena Raja, Alberto M Arenas, Anna Spinner, Kovi R Shrung, Maximilian Hornisch, Dörte Schlesinger, Carmen Navarro Luzon, Linus Brinkenstråhle, Rui Shao, Ilaria Piazza, Janne Lehtiö, Rui M M Branca, Simon J Elsӓsser.

Microproteins encoded by short open reading frames (sORFs) of <100 codons have been predicted to constitute a substantial fraction of the eukaryotic proteome. However, the relevance and roles of a majority of microproteins remain undefined, as only a small fraction of these intriguing cellular players have been characterized in-depth so far. Here, we use pooled overexpression screens with a library of 11 338 sORFs to overcome the challenge of elucidating which of the thousands of putative translated sORFs are biologically functional. As a proof-of-concept, we performed a phenotypic screen to identify sORFs protecting cells from treatment with the nucleotide analogue 6-thioguanine. With this approach, we identified two cytoprotective microproteins: altDDIT3 and PIPPI. PIPPI is encoded within the LCR16a core duplicon of the Morpheus/NPIP gene cluster. We show that PIPPI modulates the cellular response to protein folding stress in the endoplasmic reticulum (ER) and interacts with proteins in the same pathway, including protein disulfide isomerase ERp44. PIPPI overexpression protects, while PIPPI knockdown sensitizes cells to ER stress. Besides providing mechanistic insights into a new microprotein, this study highlights the power of using pooled overexpression screens to identify functional microproteins.

DOI: https://doi.org/10.1093/nar/gkaf1072

Open Biol. 2025 Nov;15(11): 250207

Bacterial infection elicits the Aedes aegypti unfolded protein response.

Dom Magistrado, Sarah M Short.

The unfolded protein response (UPR) is an ancient, highly conserved homeostatic cellular stress response pathway with diverse functions that include, but are not limited to, alleviating stress resulting from the presence of unfolded proteins in the endoplasmic reticulum of cells. Maintaining homeostasis and managing stress are critical to infection tolerance (i.e. host ability to mitigate infection-induced disease independently of strategies involving pathogen elimination). Stress responses such as the UPR are general mediators of tolerance, and the UPR may be activated during infections to promote host health. Understanding tolerance is an emerging priority in animal immunity, and there is unique motivation to understand how disease vectors tolerate infections because tolerance has implications for the efficiency of human pathogen transmission. However, stress responses are scarcely studied in arthropods, and the UPR has not been investigated in the context of a systemic mosquito infection. Herein, we characterize the trajectories of mortality and UPR transcript abundance in Aedes aegypti in response to infection with the opportunistic bacterial pathogen Serratia marcescens. We reveal that, with the exception of atf6, which displayed comparatively delayed activation, transcript levels of all UPR genes we measured harmoniously activate, peak, then diminish prior to the advent of appreciable infection-induced mortality.

Keywords: homeostasis; infection; mosquito; stress response; tolerance; unfolded protein response

DOI: https://doi.org/10.1098/rsob.250207

Cancers (Basel). 2025 Oct 30. pii: 3489. [Epub ahead of print]17(21):

The Unfolded Protein Response in Sarcomas: From Proteostasis to Therapy Resistance.

Elizabeta Ilieva, Sofia Avnet, Nicola Baldini, Margherita Cortini.

Sarcomas are a rare and heterogeneous group of malignant tumors that pose significant clinical challenges, including delayed diagnosis, therapeutic resistance, and lack of reliable biomarkers. Despite advances in surgery and chemotherapy, effective treatment options for advanced disease remain limited, underscoring the urgent need to identify novel therapeutic vulnerabilities. The unfolded protein response (UPR), a conserved cellular stress pathway that maintains proteostasis under conditions of endoplasmic reticulum stress, has emerged as a critical modulator of cancer cell fate. By regulating protein folding, redox balance, and survival pathways, the UPR exerts a dual role in tumor biology, supporting tumor growth under stress while triggering apoptosis when stress becomes sustained or severe. In sarcomas, accumulating evidence indicates that UPR activation contributes to metabolic adaptation, angiogenesis, immune evasion, and chemoresistance. Drawing on the current literature encompassing preclinical models, recent translational research (PubMed from 2000 to 2025), and registered clinical trials, this narrative review synthesizes current knowledge on the multifaceted role of the UPR in sarcoma pathogenesis, with a particular focus on osteosarcoma. Furthermore, it explores the feasibility of UPR-targeted strategies as adjuvant or combinatorial approaches. In conclusion, this review provides an integrated and in-depth analysis of UPR-mediated mechanisms in sarcomas, offering perspectives on how targeting this pathway could accelerate the development of more effective and personalized treatments.

Keywords: osteosarcoma; precision medicine; soft tissue sarcoma; tumor microenvironment; unfolded protein response

DOI: https://doi.org/10.3390/cancers17213489

Diabetologia. 2025 Nov 13.

Insulin production is sustained during DNA damage-mediated senescence in adult human beta cells.

Camille Préfontaine, Jasmine Pipella, Nayara Rampazzo Morelli, Yi-Chun Chen, C Bruce Verchere, Peter J Thompson.

AIMS/HYPOTHESIS: Residual pancreatic beta cells in type 1 diabetes show reduced insulin production but the mechanisms remain unclear. Beta cells undergo stress responses during type 1 diabetes, including endoplasmic reticulum (ER) stress and DNA damage-associated senescence, which may affect insulin production. ER stress reduces insulin production but whether senescence disrupts insulin production in human beta cells has not been investigated.
METHODS: DNA damage-mediated senescence was induced using bleomycin in human donor islets. Relative levels of prohormone convertase 1/3 (PC1/3), prohormone convertase 2 (PC2), carboxypeptidase E (CPE) and the endogenous PC1/3 inhibitor, proprotein convertase subtilisin/kexin type 1 inhibitor (proSAAS), were quantified by western blot. Levels of proinsulin and insulin were measured by ELISA. Flow cytometry was used to measure insulin expression in islet cells. FACS was used to sort endogenous senescent beta cells from islets for analysis of insulin content. Proinsulin immunofluorescence staining was quantified in endogenous senescent vs non-senescent beta cells in pancreas tissue from control donors and donors with type 1 diabetes. Publicly available datasets were used to interrogate relationships between senescence effectors, proinsulin-processing genes and insulin content. DNA damage was induced with bleomycin in the non-proliferative female-fetus-derived EndoC-βH5 human beta cell model to study the impact of the DNA damage response on insulin production in clonal cells growth-arrested due to p16INK4A expression.
RESULTS: DNA damage-mediated senescence led to increased PC1/3 without changes in levels of PC2, CPE or proSAAS in human islets. Consistent with these changes, no significant differences in proinsulin or insulin content were observed, compared with control islets. Flow cytometry confirmed maintenance of insulin content in DNA damage-mediated senescent beta cells vs control cells and sorted endogenous senescent beta cells had similar insulin content to non-senescent beta cells. Proinsulin staining was similar in endogenous senescent vs non-senescent beta cells from a control donor and donor with type 1 diabetes. Analysis of proteomics datasets from Humanislets.com and single-cell RNA-seq datasets from the Human Pancreas Analysis Program corroborated these findings. In EndoC-βH5 beta cells, which are growth-arrested, DNA damage led to decreased levels of CPE and proSAAS, and reduced levels of insulin.
CONCLUSIONS/INTERPRETATION: Our findings suggest that the expression of proinsulin-processing enzymes and the production of insulin are sustained in both chemically induced DNA damage-related senescence and in endogenous senescent adult human beta cells. Collectively, these findings suggest that senescent beta cells may be a source of insulin production among residual beta cells in type 1 diabetes.

Keywords: Type 1 diabetes; Beta cell senescence; DNA damage response; Insulin synthesis; Proinsulin processing

DOI: https://doi.org/10.1007/s00125-025-06603-3

Nat Commun. 2025 Nov 10. 16(1): 9867

Systematic characterization of the composition and dynamics of processing body-associated mRNAs.

Zhiyuan Sun, Xiaozhen Wen, Yanping Li, Xiaoxin Xie, Peng Dong, Yi Shu, Shuye Tian, Jiao Yang, Yangfan Lin, Mengran Wang, Feifei Jiang, Qionghua Zhu, Huanhuan Cui, Jixian Zhai, Yuhui Hu, Liang Fang, Wei Chen.

Processing bodies (PBs) are dynamic, membraneless organelles consisting of RNAs and proteins. While PB proteins have been extensively characterized, the methods for systematically profiling PB-associated RNAs are limited. To address this, we developed PB-TRIBE-STAMP, a tool based on two orthogonal RNA editing enzymes. Simultaneously applying APOBEC1-DDX6 and LSM14A-ADAR2dd, PB-TRIBE-STAMP identified 1,639 and 2,577 PB-associated mRNAs in HCT116 and HEK293T cells, respectively. Further biochemical isolation of PBs followed by RNA-seq validated that edited transcripts of these mRNAs were indeed enriched in PBs. Integration of PB-TRIBE-STAMP with long-read sequencing revealed that the PB-associated transcripts possessed shorter poly(A)-tails. Many mRNA 3' UTR isoforms exhibited isoform-specific PB association patterns. Moreover, we established a TRIBE-ID-based tool to characterize the mRNA-LSM14A/PB association at high temporal resolution and unveiled a higher splicing efficiency of LSM14A-associated XBP1 transcripts during unfolded protein response (UPR). Finally, based on single-cell LSM14A-TRIBE-ID (sc-LSM14A-TRIBE-ID), we demonstrated the dynamic pattern of mRNA-LSM14A/PB association during cell cycle progression.

DOI: https://doi.org/10.1038/s41467-025-64848-3