bims-unfpre 2025-09-21 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–09–21
thirteen papers selected by
Susan Logue, University of Manitoba

Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions.
Interplay of stromal cell-derived factor 2 and endoplasmic reticulum stress in the placenta: A review.
Impairment in global protein synthesis uncouples UPR gene induction from HAC1 mRNA splicing in Saccharomyces cerevisiae.
Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome.
Unresolved ER stress restricts in vitro plant cell totipotency.
Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
A Small-Molecule Activator of Sarco/Endoplasmic Reticulum Ca2+-ATPase Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress and Apoptosis.
Unique and conserved endoplasmic reticulum stress responses in neuroendocrine cells.
Endoplasmic reticulum-mitochondria dual-targeting nanoplatform suppresses cancer stemness and enhances colorectal cancer immunotherapy.
Neurons and astrocytes have distinct organelle signatures and responses to stress.
Endoplasmic reticulum-associated degradation mitigates atherosclerosis by maintaining cellular homeostasis.
Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy.
Comment on "Deciphering the Molecular Crosstalk of Endoplasmic Reticulum Stress and Immune Infiltration in Endometriosis".

FASEB J. 2025 Sep 30. 39(18): e70982

Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions.

Jia Xu, Yongli Zhang, Junmin Pan.

  Primary cilia play critical roles in development and physiology. The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, is a fundamental cellular process. However, whether and how ER stress influences ciliary assembly and function remain poorly understood. Here, we demonstrate that ER stress promotes ciliogenesis and hedgehog (HH) signaling by upregulating cholesterol levels, thereby alleviating cellular damage. IRE1 and PERK, sensors of ER stress, positively regulate ciliogenesis by enhancing the trafficking of preciliary vesicles through upregulation of cellular cholesterol levels via activation of SREBP2. Furthermore, the cholesterol content in the ciliary membrane also increases during ER stress, leading to enhanced ciliary recruitment of Smoothened (SMO) and activation of HH signaling. The activation of HH signaling via primary cilium is crucial for protecting cells from stress-induced damage. Our findings unveil a pivotal role of cilia-mediated hedgehog signaling in cell fate determination under ER stress.

Keywords:  ER stress; UPR; cholesterol; cilia or flagella; ciliogenesis; hedgehog signaling

DOI:  https://doi.org/10.1096/fj.202500391RR
Placenta. 2025 Sep 05. pii: S0143-4004(25)00681-2. [Epub ahead of print]

Interplay of stromal cell-derived factor 2 and endoplasmic reticulum stress in the placenta: A review.

E Bevilacqua, C R R Rocha, H W Yung, G J Burton, A R Lorenzon.

  Disruption of endoplasmic reticulum (ER) homeostasis causes a condition known as "ER stress" that triggers a finely regulated response, the unfolded protein response (UPR), primarily associated with the restoration of normal ER function. Although the UPR is principally a pro-survival process, sustained and/or prolonged stress can induce cell death. ER stress has been observed in various gestational diseases and is associated with poor pregnancy outcomes. In this review, we examined the role of stromal cell-derived factor 2 (SDF2) in the UPR, particularly in placental cells. We highlight recent findings that enhance our understanding of the underlying molecular mechanisms and their influence on the balance between cell survival and death. Exploring how SDF2 affects cell survival and death during ER stress may be vital for developing therapeutic strategies aimed at preventing adverse disease outcomes during pregnancy.

Keywords:  ER stress; Placenta; SDF2; Trophoblast cell lines; UPR

DOI:  https://doi.org/10.1016/j.placenta.2025.09.004
Front Microbiol. 2025 ;16 1629132

Impairment in global protein synthesis uncouples UPR gene induction from HAC1 mRNA splicing in Saccharomyces cerevisiae.

Ralph Allen Capistrano Geronimo, Yuki Ishiwata-Kimata, Yutaka Funahashi, Shingo Izawa, Yukio Kimata.

  Upon dysfunction of the endoplasmic reticulum (ER), also known as ER stress, eukaryotic cells alter their transcriptomes. This cytoprotective response is called the unfolded protein response (UPR), which is mediated by Ire1 and HAC1 in the yeast Saccharomyces cerevisiae. ER stress induces self-association and activation of the ER-resident transmembrane endoribonuclease Ire1, which catalyzes the splicing of HAC1 mRNA. It is widely accepted that HAC1 mRNA is translated into the nuclear transcription factor Hac1, only after being spliced. To investigate the cellular response to ethanol-induced ER stress, here we gradually added ethanol into S. cerevisiae cultures until reaching a final concentration of 16%. Unlike conventional ER stressors, such as tunicamycin and dithiothreitol (DTT), the ethanol exposure did not elicit the Ire1- and HAC1-dependent UPR gene induction, even though Ire1 was activated and HAC1-mRNA was efficiently spliced. Under the ethanol stress condition, global protein synthesis was nearly abolished, and the Hac1 protein level remained low, despite the presence of spliced HAC1 mRNA. Furthermore, treatment with the translation inhibitor cycloheximide abolished DTT-induced UPR gene induction. As the UPR signaling pathway requires translation of the spliced HAC1 mRNA, integrity of the translation machinery is deduced to be essential for UPR gene induction. In summary, we demonstrated that impairment of the translation machinery can actually block UPR gene induction under certain stress conditions. We also propose that this represents an advantageous regulatory system that prevents unnecessary gene induction.

Keywords:  endoplasmic reticulum; ethanol; stress response; unfolded protein response; yeast

DOI:  https://doi.org/10.3389/fmicb.2025.1629132
bioRxiv. 2025 Sep 04. pii: 2025.09.04.674221. [Epub ahead of print]

Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome.

Ya-Shiuan Lai, Jesse Chao, Maho Niwa.

Endoplasmic reticulum (ER) stress triggers activation of the ER surveillance (ERSU) pathway- a critical protective mechanism that transiently halts cortical ER inheritance to daughter cells and arrests cytokinesis by septin ring subunit Shs1 re-localization to the bud scar in response to ER stress. Once ER functional homeostasis is re-established, cells resume normal cell cycle progression; however, the molecular circuitry linking ER integrity to cell cycle regulation has remained largely unresolved. Here, we show that ER stress selectively disperse Bud2, a GAP for Bud1/Rsr1, severing its canonical role in cell polarity while integrating it into ER homeostasis signaling. Bud2 dispersion results in accelerated spindle pole body (SPB) duplication, spindle misorientation, defects in nuclear migration, and genome segregation errors under ER stress. Strikingly, a C-terminal truncation of Shs1 ( shs1-ΔCTD ) recapitulated the ER stress-induced dispersion of Bud2 phenotype even in the absence of ER stress, and delayed cell-cycle re-entry after ER homeostasis was regained-despite normal occurrence of typical ERSU hallmark events. Notably, Bud2 overexpression rescued the growth defects of shs1-ΔCTD mutants after ER homeostasis was re-established. Collectively, our findings reveal a new mechanistic axis whereby ER integrity coordinates organelle inheritance, cytoskeletal organization, and nuclear division via selective control of Bud2 and Shs1, establishing a direct regulatory bridge between ER status and mitotic fidelity.

DOI: https://doi.org/10.1101/2025.09.04.674221
Plant Cell Rep. 2025 Sep 17. 44(10): 214

Unresolved ER stress restricts in vitro plant cell totipotency.

Patricia Corral Martinez, Charlotte Siemons, Michael Schon, Marije Vos, Anneke Horstman, Ruud de Maagd, Jose María Seguí-Simarro, Kim Boutilier.

   KEY MESSAGE: Many plant cells can be induced to regenerate in vitro. We show that successful regeneration during microspore-derived embryo culture relies in part on the ability of embryogenic cells to resolve tissue culture-induced ER stress. During Brassica napus microspore embryogenesis, the immature male gametophyte is induced by a heat stress treatment to develop into a haploid embryo. Different multicellular embryogenic structures develop in response to heat stress, each with a different potential to complete embryo development. The underlying factors that determine the ability of these initially embryogenic structures to successfully complete embryo development are not known. We show that all embryogenic structures exhibit elements of endoplasmic reticulum (ER) stress, like ER expansion and protein-filled ER cisternae, but that the ER stress response is amplified in embryogenic structures with a low potential to complete embryo development. ER stress was amplified even further by treating heat-stressed cultures with trichostatin A, a histone deacetylase inhibitor epidrug that promotes embryogenic cell formation. Pharmacological treatment of microspore-derived embryo cultures with small molecule modulators of ER stress provided further evidence for the role of ER stress in microspore embryo development. Our results suggest that (1) the inability of certain embryogenic structures to resolve their ER stress responses restricts their ability to complete embryo development, and (2) histone deacetylation enhances microspore embryogenesis in B. napus, in part through its activity as an abiotic stress inducer.

Keywords:   Brassica napus ; ER stress; Microspore embryogenesis; Totipotency

DOI:  https://doi.org/10.1007/s00299-025-03586-8
bioRxiv. 2025 Sep 08. pii: 2025.09.07.674755. [Epub ahead of print]

Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.

Hyunjoo Choi, Sang-Eun Jung, Hyojung Paik, Maggie J Cox, Stephen T Oh, Yoon-A Kang.

Unfolded protein response (UPR) is an evolutionally conserved adaptive mechanism that promotes protein homeostasis under endoplasmic reticulum (ER) stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcγR - MPP3 generates erythroid lineage and Jak2 V617F mutation leads to overproduction of erythroid cells by expanding FcγR - MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcγR - MPP3 transition to granulocyte/macrophage progenitor (GMP) producing FcγR + MPP3. Under a disease condition, UPR signaling cooperates with Jak2 V617F mutation and exacerbates disease phenotype as increasing red blood cells in a mouse model of polycythemia vera (PV). Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.
Highlights: UPR signaling promotes myeloid cell production. UPR signaling collaborates with Jak2 V617F mutation and increases red blood cell production.

DOI: https://doi.org/10.1101/2025.09.07.674755
ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2953-2963

A Small-Molecule Activator of Sarco/Endoplasmic Reticulum Ca2+-ATPase Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress and Apoptosis.

Vikrant Rahi, Ravinder K Kaundal.

  Calcium (Ca2+) homeostasis is critical for neuronal survival and function, which is regulated by a network of Ca2+-handling proteins. Among these, the sarco/endoplasmic reticulum calcium ATPase (SERCA) pump, located on the SR/ER membrane, plays a pivotal role in sequestering Ca2+ into the ER, thereby maintaining low cytosolic Ca2+ levels. Dysregulated SERCA function during ischemia contributes to ER Ca2+ depletion, resulting in intracellular Ca2+ imbalance and ER stress, both of which are implicated in the pathogenesis of ischemic reperfusion injury; SERCA has thus emerged as a potential pharmacological target for ischemic stroke. CDN1163, a SERCA activator, has shown promising effects in preclinical studies of neurodegenerative diseases by alleviating ER stress and restoring the Ca2+ balance. This study investigates the neuroprotective potential of CDN1163 against cerebral ischemia-reperfusion (IR) injury using middle cerebral artery occlusion (MCAO) in rats. CDN1163 treatment (10 mg/kg, i.p.) significantly improved neurological scores, motor function, and behavior, while reducing infarct volume, brain edema, and oxidative stress by decreasing nitrite and lipid peroxidation and restoring glutathione levels. Histological analysis revealed reduced neuronal damage in the cortex, subcortex, and hippocampus regions. CDN1163 restored SERCA2b and 1a expression and mitigated ER stress by decreasing the expression of ER stress markers, such as PDI, BiP, p-IRE1α, XBP1, p-PERK, p-eIF2α, ATF4, and ATF6. Furthermore, CDN1163 downregulated pro-apoptotic markers Bax and CHOP, while upregulating the antiapoptotic protein Bcl-2 with TUNEL assay confirming decreased apoptosis. These outcomes highlight that CDN1163 is a potential therapeutic candidate for ischemic stroke, as it restores SERCA expression, alleviates endoplasmic reticulum stress, reduces oxidative stress, and inhibits apoptosis.

Keywords:  cerebral ischemia-reperfusion injury; endoplasmic reticulum stress; middle cerebral artery occlusion; neuronal apoptosis; oxidative stress; sarco endoplasmic reticulum Ca2+-ATPase

DOI:  https://doi.org/10.1021/acsptsci.5c00151
bioRxiv. 2025 Sep 02. pii: 2025.08.29.672971. [Epub ahead of print]

Unique and conserved endoplasmic reticulum stress responses in neuroendocrine cells.

Karina Rodrigues-Dos-Santos, Gitanjali Roy, Anna Geisinger, Sahiti Somalraju, Travis S Johnson, Michael A Kalwat.

  Endocrine cells are dedicated to the production and processing of hormones, from peptides to small molecules, to regulate key physiological processes, including glucose homeostasis and metabolism. Because of this relatively high productivity, endocrine cells must handle a variety of stresses from oxidative stress to the unfolded protein response of the endoplasmic reticulum (UPRER). While much is known about the major pathways regulating the UPRER, the roles of endocrine cell type-specific, context-dependent, and time-dependent transcriptional changes are not well explored. To identify unique and shared responses to the UPRER across a subset of endocrine cell types, we tested representative lines for β-cells (insulin), α-cells (glucagon), δ-cells (somatostatin), X/A-cells (ghrelin), L-cells (glucagon-like peptide 1 (GLP1)), and thyrotropes (thyroid hormone and thyroglobulin). We exposed each cell type to the canonical ER stressor thapsigargin for 6 and 24 h, or vehicle for 24 h and performed mRNA sequencing. Analysis of the data showed all lines responded to thapsigargin. Comparisons of differentially expressed genes between each line revealed both shared and unique transcriptional signatures. These data represent a valuable mineable set of candidate genes that may have cell type-specific functions during the UPRER and have the potential to lead to a new understanding of how different endocrine cells mitigate or succumb to ER stress.

Keywords:  ER stress; computational biology; endocrinology; hormone secretion

DOI:  https://doi.org/10.1101/2025.08.29.672971
J Control Release. 2025 Sep 11. pii: S0168-3659(25)00842-9. [Epub ahead of print]387 114230

Endoplasmic reticulum-mitochondria dual-targeting nanoplatform suppresses cancer stemness and enhances colorectal cancer immunotherapy.

Yilin Wang, Wenting Cheng, Yang Chen, Hailong Tian, Canhua Huang, Ka Li.

  Cancer stemness in colorectal cancer (CRC) drives immune evasion and fosters an immunosuppressive tumor microenvironment (TME), limiting the efficacy of immunotherapy. To counteract this stemness-driven immune evasion, we developed a hyaluronic acid (HA) surface-modified dual-targeting nanoplatform (HA/pCe6-Ato NPs) that induces both endoplasmic reticulum stress and mitochondrial dysfunction. HA functionalization facilitates tumor-specific targeting via CD44 receptor-mediated endocytosis. The nanoplatform incorporates an ER-targeting photosensitizer, pCe6, synthesized by conjugating Chlorin e6 with p-Toluenesulfonamide, and the mitochondrial respiratory chain inhibitor atovaquone (Ato), which self-assembles into nanoparticles. Upon activation, HA/pCe6-Ato NPs induce ER stress and mitochondrial dysfunction, disrupting cancer stemness and reprogramming the immunosuppressive TME. Preclinical evaluations showed that HA/pCe6-Ato NPs promote apoptosis and accelerate reactive oxygen species production in cancer stem-like cells (CSCs), while reducing immunosuppressive factor secretion and enhancing immune effector cell infiltration. These effects synergistically enhance the efficacy of immunotherapy, achieving superior tumor inhibition compared with conventional monotherapies. Collectively, HA/pCe6-Ato NPs highlight the potential of organelle-targeting strategies to dismantle cancer resilience mechanisms, providing a foundation for dual-targeting nanomedicines to overcome resistance and enhance immunotherapy in CRC.

Keywords:  ER stress; Immunotherapy; Mitochondrial dysfunction; Organelle-targeting; Photodynamic therapy; Stemness

DOI:  https://doi.org/10.1016/j.jconrel.2025.114230
Cell Rep. 2025 Sep 15. pii: S2211-1247(25)01051-4. [Epub ahead of print]44(9): 116280

Neurons and astrocytes have distinct organelle signatures and responses to stress.

Shannon N Rhoads, Weizhen Dong, Chih-Hsuan Hsu, Ngudiankama R Mfulama, Ridhi Yarlagadda, Joey V Ragusa, Michael Ye, Andy Henrie, Maria Clara Zanellati, Graham H Diering, Todd J Cohen, Sarah Cohen.

  Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live neural cells has not been performed. Here, we use multispectral imaging to simultaneously visualize six organelles-endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets-in live primary rodent neurons and astrocytes. We generate a dataset of 173 z stack and 98 time-lapse images, accompanied by quantitative "organelle signature" analysis. Comparative analysis reveals a clear cell-type specificity in organelle morphology and interactions. Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell-type-specific physiology and disease.

Keywords:  CP: Cell biology; CP: Neuroscience; Golgi; astrocytes; endoplasmic reticulum; lipid droplets; lysosomes; microscopy; mitochondria; neurons; organelles; peroxisomes

DOI:  https://doi.org/10.1016/j.celrep.2025.116280
Front Physiol. 2025 ;16 1638694

Endoplasmic reticulum-associated degradation mitigates atherosclerosis by maintaining cellular homeostasis.

Haiming Niu, Lin Wu, Yingzhang Cai, Conghui Yu, Ning Lin, Xiaodong Cai, Miaolian Chen, Linli Wang.

  Atherosclerosis (AS) is a fatal cardiovascular disease (CVD) that threatens human health. Although there are some treatments for AS in clinical practice, cardiovascular complications such as myocardial ischemia and hypoxia, heart failure, and stroke often occur in different AS subgroups. Therefore, it is critical and necessary to screen and identify novel protein molecules to mitigate this disease. Unstable plaques of AS is the main cause for fatal consequences, so it is particularly urgent to find a treatment to stabilize plaques to prevent cardiovascular and cerebrovascular diseases. During the formation of plaque, a large amount of protein is produced and misfolded; this process initiates endoplasmic reticulum stress (ERS). Despite unfolded protein response (UPR) in the clearing of unfolded proteins, endoplasmic reticulum (ER)-associated degradation (ERAD) maintains ER proteostasis in mammalian cells by degrading misfolded proteins. However, the role of ERAD has not been fully elucidated in AS. In this review, the role of ERS in the different cells that took part in AS was summarized; then, the rescue function of ERAD in all the cell types was elucidated, especially vascular smooth muscle cells. An updated summary of the recent studies and systematic knowledge of ERAD in the mechanism of AS was presented, which may help guide future research and provide novel insights into the prevention and treatment of related diseases.

Keywords:  ERAD; ERS; Hrd1; atherosclerosis; vascular smooth muscle cell

DOI:  https://doi.org/10.3389/fphys.2025.1638694
Front Microbiol. 2025 ;16 1648467

Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy.

Hua Wang, Mengyan Li, Qiuyue Wang, Huihai Zhao, Mengyu Jiang, Qi Cui, Daxin Lei, Keran Jia, Fukun Wang.

   Introduction: Candida albicans is a common opportunistic pathogen responsible for both superficial and invasive infections. The unfolded protein response, triggered by endoplasmic reticulum stress, plays a crucial role in its survival and pathogenicity, with the endoplasmic reticulum stress sensor Ire1 serving as a key regulator. Pharmacological inhibition of Ire1 may therefore represent a novel antifungal strategy.
Methods: We conducted molecular docking to identify small-molecule inhibitors targeting the RNase activity of Candida albicans Ire1, followed by in vitro assays assessing pathogenic traits and in vivo validation using a murine intestinal colonization model.
Results: Three candidate inhibitors-MKC8866, STF083010, and 4μ8c-were predicted to interact with Ire1, but only 4μ8c exhibited consistent inhibitory activity. 4μ8c was found to significantly impair key pathogenic traits, including morphological transformation, adhesion, flocculation, and biofilm formation. Additionally, it enhanced the susceptibility of Candida albicans to antifungal drugs and reduced the expression of virulence-related genes. In vivo studies using a murine intestinal colonization model demonstrated that 4μ8c effectively reduced fungal colonization and intestinal tissue damage caused by Candida albicans.
Discussion: These findings demonstrate that pharmacological targeting of the UPR pathway through Ire1 inhibition is feasible. 4μ8c emerges as a promising candidate that diminishes the adaptability and pathogenicity of Candida albicans, offering new insights into antifungal therapeutic development.

Keywords:  4μ8c; Candida albicans; Ire1; Ire1 inhibitor; endoplasmic reticulum; pathogenicity

DOI:  https://doi.org/10.3389/fmicb.2025.1648467
Am J Reprod Immunol. 2025 Sep;94(3): e70158

Comment on "Deciphering the Molecular Crosstalk of Endoplasmic Reticulum Stress and Immune Infiltration in Endometriosis".

Saraswati Sah, Renu Sah.



Keywords:  biomarker validation; endometriosis; endoplasmic reticulum stress; immune infiltration; transcriptomics

DOI:  https://doi.org/10.1111/aji.70158