bims-unfpre 2025-12-28 papers

Issue of 2025–12–28
six papers selected by
Susan Logue, University of Manitoba

Front Physiol. 2025 ;16 1722417

Inositol-requiring enzyme 1 alpha is essential for dentinogenesis.

Qian Xu, Tian Liang, Jiahe Li, Suzhen Wang, Hua Zhang, Julie Hollien, Takao Iwawaki, Chunlin Qin, Yongbo Lu.

Introduction: Inositol-requiring enzyme 1 alpha (IRE1α), encoded by endoplasmic reticulum (ER) to nucleus signaling 1 (Ern1) gene, is the most conserved sensor of ER stress. IRE1α-initiated signaling pathways contribute to functional maturation of secretory cells and have been implicated in various human diseases. In this study, we examined the roles of IRE1α in odontoblast development and dentin formation in wild-type mice as well as in Dspp P19L mutant mice, which express a pathogenic variant of dentin sialophosphoprotein (P19L-DSPP) and exhibit a dentinogenesis imperfecta (DGI)-like phenotype.
Methods: Western-blotting and stains-all staining analyses were used to assess whether secretion of mutant P19L-DSPP was impaired in dental pulp cells containing odontoblasts from Dspp P19L/P19L mice compared with Dspp +/+ controls. Immunohistochemistry and reverse-transcription PCR were performed to examine changes in IRE1α and its downstream target X-box binding protein 1 (XBP1) in P19L-DSPP mutant mice. To further investigate the roles of IRE1α in tooth development, we generated 2.3 Col1-Cre;Ern1 fl/fl and compound 2.3 Col1-Cre;Ern1 fl/fl ;Dspp P19L/+ mice. Structural and histological changes in mandibular molars were analyzed using plain X-ray radiography, micro-computed tomography (µCT), and histology. Additionally, in situ hybridization, quantitative real-time PCR, and immunohistochemistry were performed to compare molecular changes among these mice and Ern1 fl/fl and Ern1 fl/fl ;Dspp P19L/+ controls.
Results: Western-blotting and stains-all staining analyses support that mutant P19L-DSPP protein was not efficiently secreted into dentin matrix and was accumulated within odontoblasts. Further, immunostaining signals for phosphorylated IRE1α and total XBP1 were dramatically increased in odontoblasts and other dental pulp cells of Dspp P19L/+ and Dspp P19L/P19L mice, in comparison with Dspp +/+ mice. Consistently, there was a small increase in spliced XBP1S protein and Xbp1s mRNA levels in P19L-DSPP mutant mice. Moreover, loss of IRE1α function reduced dentin formation in 2.3 Col1-Cre;Ern1 fl/fl mice and exacerbated the dental defects of P19L-DSPP mutant mice. Notably, IRE1α deficiency did not restore the Dspp mRNA levels in the mutant mice but normalized the increased thickness of the dental pulp chamber floor dentin.
Conclusion: These findings underscore the essential role of IRE1α in odontoblast function and dentinogenesis. Moreover, they reveal a context-dependent pathogenic role of IRE1α, providing new insights into ER stress in dental tissue development and disease.

Keywords: dentin formation; dentin sialophosphoprotein (DSPP); dentinogenesis imperfecta (DGI); inositol-requiring enzyme 1 alpha (IRE1α); odontoblast; unfolded protein response (UPR)

DOI: https://doi.org/10.3389/fphys.2025.1722417

Cell Stress Chaperones. 2025 Dec 18. pii: S1355-8145(25)00086-0. [Epub ahead of print] 100141

Expanding the landscape of the unfolded protein response: the roles of secondary transcription factors in development and disease.

Miguel Angel Jiménez-Beltrán, Rocío Valle-Bautista, Edgar Ricardo Vázquez-Martínez.

The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a classic cellular reaction to stress that helps restore ER homeostasis. However, growing evidence demonstrates that the main UPR effectors (ATF6, XBP1s, and ATF4) not only regulate canonical UPR target genes but also promote the transcription of genes encoding secondary transcription factors (TFs). These secondary TFs contribute to ER homeostasis maintenance and are involved in various physiological processes that extend beyond the traditional UPR. In this review, we examine the secondary TFs activated by UPR master regulators (UPR-TFs) and discuss their functional roles in different tissues and organs. We emphasize how these secondary TFs, controlled by their respective UPR-TFs, participate in stress responses, cell differentiation, embryonic development, circadian rhythms, metabolism, and other physiological processes. Furthermore, we explore common signaling pathways and tissue and cell-specific regulatory mechanisms, highlighting convergence points where secondary TFs from different UPR branches intersect, indicating a more complex regulatory network. We also discuss the functions of these secondary TFs in the lungs, placenta, testis, uterus, pancreas, and liver, as well as during embryonic development and in pathological conditions. This study reveals biological activities that extend beyond the traditional roles of the UPR, providing a broader view of this signaling pathway and opening new avenues for future research.

Keywords: ATF4; ATF6; Transcription Factor; UPR; XBP1

DOI: https://doi.org/10.1016/j.cstres.2025.100141

J Biol Chem. 2025 Dec 18. pii: S0021-9258(25)02919-9. [Epub ahead of print] 111067

Direct Optical Activation of Human IRE1 Identifies Unique Patterns of Transcriptional and Post-Transcriptional mRNA Regulation in the Unfolded Protein Response.

Jacob W Smith, Damien B Wilburn, Vladislav Belyy.

Inositol-requiring enzyme 1 (IRE1) is one of three known sensor proteins that respond to homeostatic perturbations in the metazoan endoplasmic reticulum. The three sensors collectively initiate an intertwined signaling network called the Unfolded Protein Response (UPR). Although IRE1 plays pivotal roles in human health and development, understanding its specific contributions to the UPR remains a challenge due to signaling crosstalk from the other two stress sensors. To overcome this problem, we engineered a light-activatable version of IRE1 and probed the transcriptomic effects of IRE1 activity in isolation from the other branches of the UPR. We demonstrate that 1) oligomerization alone is sufficient to activate IRE1 in human cells, 2) IRE1's transcriptional response evolves substantially under prolonged activation, and 3) the UPR induces major changes in mRNA splice isoform abundance in an IRE1-independent manner. Our data reveal previously unknown targets of IRE1's transcriptional regulation and direct degradation. Additionally, the tools developed here will be broadly applicable for precise dissection of the UPR in diverse cell types, tissues, and organisms.

DOI: https://doi.org/10.1016/j.jbc.2025.111067

Anal Chem. 2025 Dec 22.

Monitoring Endoplasmic Reticulum Stress Using Self-Targeting Water-Activated Pure Afterglow Luminescence Materials.

Ya Ting Gao, Ming Jie Ye, Han Bin Xu, Li Ya Liang, Ying Zhang, Mahmoud Elsayed Hafez, Ruo Can Qian, Bin Bin Chen, Da Wei Li.

The endoplasmic reticulum (ER) plays a critical role in regulating diverse cellular processes. Monitoring ER behavior under cellular stress is of great significance, however, time-gated afterglow imaging of ER physiology remains challenging due to the water-quenching effect on triplet excitons. Herein, we have developed a water-activated crystallization engineering strategy to achieve pure afterglow luminescence (PAL) in carbon dots-doped B2O3 matrices (CDs@B2O3) for ER stress afterglow imaging. In their dry state, CDs@B2O3 exhibit strong prompt fluorescence (PF) and room-temperature phosphorescence (RTP). Notably, the introduction of water induces the transformation of amorphous B2O3 matrices into highly crystalline boric acid (BA) matrices, resulting in the formation of CDs@BA with a rigid structure. This crystalline transition completely suppresses PF, enabling high-performance PAL through intense thermally activated delayed fluorescence (TADF) with a record-breaking lifetime of 632.0 ms. Furthermore, owing to the strong ER affinity of BA groups and their efficient aqueous afterglow performance, CDs@BA are particularly suitable for high-contrast, self-targeting imaging of the ER in living cells, while effectively eliminating autofluorescence interference. The imaging results clearly demonstrate that the ER can be effectively degraded by lysosomes under nutrient deprivation stress. This work not only develops an effective crystallization engineering strategy to achieve efficient aqueous PAL, but also provides a valuable tool for studying cellular physiology under ER stress.

DOI: https://doi.org/10.1021/acs.analchem.5c05746

Cell Signal. 2025 Dec 19. pii: S0898-6568(25)00748-X. [Epub ahead of print] 112333

PERK-eIF2alpha-mediated translational inhibition of MCL-1 contributes to potential 2-deoxy-d-glucose and BAD mimetic combinatorial cancer therapy.

Mengning Sun, Li Li, Rongrong Fu, Qinglan Yang, Wenjuan Chen, Yi Sun, Hui Gao, Hang Gao, Na Dong.

Glycolysis inhibitor 2-Deoxy-d-glucose (2DG) has been extensively studied as a potential therapeutic agent because tumors depend more on aerobic glycolysis than normal cells for their energy supply. However, the precise mechanism underlying 2DG's toxicity remains not so clear. In this study, we confirmed that 2DG induces apoptosis primarily by disrupting glycosylation rather than glycolysis. We observed that glucose depletion or 2DG treatment leads to a significant reduction of MCL-1 protein levels. Further analysis revealed that 2DG toxicity required MCL-1 degradation. Moreover, through knocking out experiments, BAD was identified as the only BH3-only protein essential for 2DG-induced apoptosis. The downregulation of MCL-1, combined with the dephosphorylation of BAD at Serine 155, contribute to the simultaneous inactivation of the anti-apoptotic functions of both MCL-1 and BCL-xL, which is sufficient to induce 2DG toxicity. Additionally, our experiments showed that Endoplasmic Reticulum (ER) stress induced PERK-eIF2α pathway mediated translational inhibition of MCL-1 contributes to 2DG toxicity. Based on these findings, the combined use of 2DG with BAD BH3 mimetic have proven effective against various types of cancer cells. In conclusion, this study provides a theoretical basis and rationale for the combined use of 2DG and BH3 mimetics as a promising therapeutic strategy for cancers.

Keywords: Apoptosis; BAD; Dephosphorylation; Glycolysis inhibitor; Glycosylation; MCL-1

DOI: https://doi.org/10.1016/j.cellsig.2025.112333

Cell Stress Chaperones. 2025 Dec 19. pii: S1355-8145(25)00088-4. [Epub ahead of print] 100143

Defective Mitochondrial Unfolded Protein Response in Cancer Acts as a Lifeline for Tumor Growth and Survival.

Uttam Sharma, Vaishnavi Vishwas, Rajiv Ranjan Kumar, Nikita Agarwal, Akshi Shree, Jaya Kanta Gorain, Archana Sasi, Surender K Sharawat, Archna Singh, Jayanth Kumar Palanichamy, Sameer Bakhshi.

Defective mitochondrial unfolded protein response (UPRmt plays an important role in driving tumor growth and treatment resistance. Under physiological conditions, UPRmt preserves mitochondrial protein homeostasis and structure by inducing chaperones such as heat shock proteins (HSP60, HSP70, HSP10) and proteases like caseinolytic peptidase ATP-dependent, proteolytic subunit (ClpP), and Lon peptidase 1 (LONP1). However, dysfunctional UPRmt in cancer cells may allow them to tolerate mitochondrial damage and metabolic dysregulation, and avoid cell death, thus promoting therapy resistance. Our current understanding of how transcriptional regulators such as activating transcription factor 5 (ATF5), C/EBP homologous protein (CHOP), and forkhead box protein O3a (FOXO3a), along with signaling circuits including ATF5-ATF4-CHOP, SIRT3-FOXO3a and AKT-ERα, coordinate detrimental forms of UPRmt activation in cancer cells remains limited. This review describes known interactions among mediators of the UPRmt pathway and how they may be dysregulated in cancer cells. We also explore how this altered stress response may provide avenues for therapeutic targeting.

Keywords: Cancer; Chaperones; Mitochondrial unfolded protein response; Proteases; UPRmt

DOI: https://doi.org/10.1016/j.cstres.2025.100143