bims-unfpre 2025-09-14 papers

Issue of 2025–09–14
four papers selected by
Susan Logue, University of Manitoba

Cell Stress Chaperones. 2025 Sep 09. pii: S1355-8145(25)00058-6. [Epub ahead of print] 100113

TBX5-AS1 induces ER stress and suppresses lung cancer growth and tumor stemness via the miR-494-3p/ATF6 axis.

Guoqin Wang, Chaojiang Fu, Changling Tu, Zhuangqing Yang, Wei Shi, Lijuan Zhang, Shufen Tan, Youguang Huang.

Tumor stemness maintenance and endoplasmic reticulum (ER) stress response have been strongly correlated with the progression of LC. Nevertheless, the role of long non-coding RNAs (lncRNAs) in these processes remains incompletely understood. We screened LC-associated lncRNAs from the GEO database and validated the expression of TBX5-AS1 in clinical samples. Functional experiments were conducted to assess the biological effects of TBX5-AS1, and western blot was used to detect ER stress marker proteins. The interaction mechanism of the TBX5-AS1/miR-494-3p/ATF6 axis was elucidated through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and pull-down experiments. Rescue experiments and a nude mouse xenograft model were employed to validate the functional outcomes. TBX5-AS1 was significantly downregulated in LC tissues and cell lines, and its low expression was associated with advanced tumor stages and poor patient prognosis. Overexpression of TBX5-AS1 markedly suppressed LC cell proliferation, migration, invasion, and self-renewal while promoting the activation of ER stress pathway. Mechanistically, TBX5-AS1 competitively binds to miR-494-3p, thereby relieving its transcriptional repression of ATF6. Rescue experiments demonstrated that miR-494-3p overexpression reversed the regulatory effects of TBX5-AS1 on tumor malignant phenotype and ER stress. In vivo experiments further confirmed that TBX5-AS1 overexpression significantly inhibited tumor growth, accompanied by upregulation of ATF6 and ER stress-related proteins. TBX5-AS1 functioned as a tumor-suppressive lncRNA by activating ER stress signaling through the miR-494-3p/ATF6 axis, thereby inhibiting LC growth and tumor stemness.

Keywords: ATF6; ER stress; TBX5-AS1; miR-494-3p; tumor stemness

DOI: https://doi.org/10.1016/j.cstres.2025.100113

Genetics. 2025 Sep 11. pii: iyaf190. [Epub ahead of print]

A novel role for the E2F transcription factor and the ER stress sensor IRE1 in cytoplasmic DNA accumulation.

Arghya Das, Yining Li, Yiting Fan, Nam-Sung Moon.

The E2F family of transcription factors are key regulators of the cell cycle in all metazoans. While they are primarily known for their role in cell cycle progression, E2Fs also play broader roles in cellular physiology, including the maintenance of exocrine tissue homeostasis. However, the underlying mechanisms that render exocrine cells particularly sensitive to E2F deregulation remain poorly understood. The Drosophila larval salivary gland (SG), like its mammalian counterpart, is an exocrine tissue that produces large quantities of "glue proteins" in the endoplasmic reticulum (ER). Here, we show that E2F activity is important for the exocrine function of the Drosophila SG. The loss of de2f1b, an alternatively spliced isoform of Drosophila E2F1, leads to elevated DNA damage and accumulation of cytoplasmic DNA (cytoDNA) in the SGs. Surprisingly, we found that IRE1, a key sensor of the unfolded protein response, is required for ER homeostasis during development that is critical for preventing cytoDNA accumulation in the SG. Importantly, we found evidence demonstrating that IRE1 activity is attenuated in de2f1b-deficient SGs, contributing to ER dysfunction and cytoDNA accumulation. Together, these findings reveal an unanticipated link between ER homeostasis and cytoDNA processing and offer mechanistic insights into why exocrine tissues are particularly vulnerable to E2F deregulation.

Keywords: Cytoplasmic DNA; Drosophila; E2F; Endocycle; Endoplasmic reticulum; IRE1; Unfolded Protein Response

DOI: https://doi.org/10.1093/genetics/iyaf190

Biochim Biophys Acta Mol Cell Res. 2025 Sep 08. pii: S0167-4889(25)00164-8. [Epub ahead of print] 120059

SYK overexpression enhances microtubule instability in an MDA-MB-231-derived paclitaxel-resistant cell line.

Hsiao-Hui Kuo, Chien-Wei Huang, Wei-Rou Chiang, Chieh-Ting Fang, Shang-Yuan Liu, Ling-Huei Yih.

Paclitaxel resistance is a major obstacle to achieving long-term remission in patients with triple-negative breast cancer (TNBC), and effective strategies to overcome drug resistance would have significant clinical impact. In this study, we established a paclitaxel-resistant cell clone, T50R, from the human TNBC cell line MDA-MD-231. Intriguingly, these drug-resistant T50R cells required paclitaxel for proliferation. When cultured in the absence of drug, the cells exhibited high dynamic instability of microtubules (MTs) and spindle abnormalities, causing their accumulation in mitosis phase and cell death. Thus, the increased instability of MTs in T50R cells may contribute to the drug requirement for cell growth and drug-resistant phenotype, as paclitaxel counteracts the effect. Compared to the parental MDA-MD-231 cells, T50R cells had elevated expression of spleen tyrosine kinase (SYK), and inhibition or depletion of SYK in the T50R cells cultured without paclitaxel restored MT stability, reduced spindle defects and rescued cell death, suggesting that SYK overexpression contributes to the enhanced MT instability in T50R cells. Furthermore, T50R cells exhibited signs of ER stress and underwent ferroptotic cell death when cultured without paclitaxel, both of which could be ameliorated by inhibition of SYK. Finally, small molecules that target SYK or induce ferroptosis could significantly enhance T50R cell sensitivity to paclitaxel. Together, our results show that SYK-enhanced MT dynamic instability can play an important role in paclitaxel resistance and that targeting the SYK pathway may enhance paclitaxel response.

Keywords: Cell death; ER stress; Microtubule instability; Paclitaxel resistance; SYK

DOI: https://doi.org/10.1016/j.bbamcr.2025.120059

FASEB J. 2025 Sep 15. 39(17): e71025

The IRE1/XBP1s Axis Regulates Innate Immune Responses in Conventional Dendritic Cells During ZIKV Infection.

Mónica Guzmán-Rodríguez, Tomás Hernández-Díaz, Paula Lisboa, Javier López-Schettini, Sofia Sanhueza, Lisette Leyton, Takao Iwawaki, Ricardo Soto-Rifo, Fabiola Osorio.

Zika virus (ZIKV) is a mosquito-borne flavivirus causing a major epidemic in the Americas in 2015. Dendritic cells (DCs) are leukocytes with key antiviral functions, but their role in ZIKV infection remains under investigation. While most studies have focused on the monocyte-derived subtype of DCs, less is known about conventional dendritic cells (cDCs), essential for the orchestration of antiviral adaptive immunity. This study investigates the mechanisms by which cDCs respond to ZIKV for antiviral cytokine production. Here, using murine cultures, we demonstrate that ZIKV infection and not detection of ZIKV-infected dead cells activates cDCs by inducing type I interferons (IFN-I) and proinflammatory cytokines. Furthermore, ZIKV-infected cDCs markedly activated the IRE1/XBP1s axis of the unfolded protein response (UPR). Flow cytometry analysis indicates that among cDCs, type 1 cDCs (cDC1s) are responsible for ZIKV detection. Functionally, genetic loss of XBP1s curtailed expression of the costimulatory molecule CD86 and the production of IFN-I and proinflammatory cytokines by cDCs, without exhibiting increased susceptibility to ZIKV infection. These effects are attributable to perturbations in the IRE1/XBP1s axis and not due to overcompensation of PERK or IRE1 kinase signaling. Finally, tissue resident cDCs also exhibit susceptibility to infection, potentially establishing these cells as ZIKV targets in vivo. These findings underscore a critical role for the IRE1/XBP1s pathway in fine-tuning cDC activation to ZIKV, linking viral recognition to cDC functional maturation and opening new avenues for exploring UPR pathways targeting cDCs in the context of flavivirus infections.

Keywords: IRE1; XBP1; Zika virus; cDC1; dendritic cells; unfolded protein response

DOI: https://doi.org/10.1096/fj.202501186R