bims-unfpre 2025-06-15 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–06–15
eight papers selected by
Susan Logue, University of Manitoba

Integrin-Specific Signaling Drives ER Stress-Dependent Atherogenic Endothelial Activation.
Importance of unfolded protein response modulation on diabetes management: a systematic review.
Impact of ATF6 deletion on the embryonic brain development.
SEL1L Regulates ER Homeostasis in Sertoli Cells but Is Dispensable for Their Function.
ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.
Single-cell transcriptomics showed that maternal PCB exposure dysregulated ER stress-mediated cell type-specific responses in the liver of female offspring.
Celastrol improves endothelial function in diet-induced obesity mice via attenuating endoplasmic reticulum stress through the activation of AMPK pathway.
VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.

bioRxiv. 2025 Jun 01. pii: 2025.05.31.654582. [Epub ahead of print]

Integrin-Specific Signaling Drives ER Stress-Dependent Atherogenic Endothelial Activation.

Cyrine Ben Dhaou, Zaki Al-Yafeai, G Ali Cruz-Marquez, Matthew L Scott, Brenna Pearson-Gallion, Elizabeth Cockerham, Hanna Li, Jonette M Peretik, Yuning Hong, Nirav Dhanesha, Arif Yurdagul, Oren Rom, Md Shenuarin Bhuiyan, A Wayne Orr.

Atherogenic endothelial activation arises from both the local arterial microenvironment-characterized by altered extracellular matrix composition and disturbed blood flow-and soluble proinflammatory stimuli such as oxidized low-density lipoprotein (oxLDL). Fibronectin, a provisional extracellular matrix protein enriched at atheroprone sites, enhances endothelial activation and inflammation triggered by oxLDL and disturbed flow. Although endoplasmic reticulum (ER) stress contributes to vascular dysfunction, the role of matrix composition in regulating ER stress remains unknown. We show that oxLDL and disturbed flow induce ER stress selectively in endothelial cells adhered to fibronectin, whereas both stimuli fail to induce ER stress in cells on basement membrane proteins. This matrix-specific ER stress response requires integrin activation, as endothelial cells deficient for integrin activation (talin1 L325R mutation) fail to activate ER stress in response to disturbed flow and oxLDL and direct stimulation of integrin activation using CHAMP peptides is sufficient to trigger ER stress. Blunting endothelial expression of fibronectin-binding integrins (α5, αv) using siRNA prevents ER stress in response to atherogenic stimuli in vitro , whereas endothelial α5 and αv deletion reduces ER stress at atheroprone sites in vivo . The mechanisms driving integrin-dependent ER stress remain unclear, since matrix composition does not affect protein translation, unfolded protein accumulation, or superoxide production, and scavenging superoxide (TEMPOL) does not reduce integrin-dependent ER stress. Inhibiting ER stress with TUDCA reduces proinflammatory and metabolic gene expression (bulk RNAseq) but does not prevent NF-κB activation, a classic proinflammatory transcription factor. Rather, TUDCA prevents activation of c-jun N-terminal kinase (JNK) and c-jun activation, and blocking JNK (SP600126) or c-Jun activity (TAM67) prevents proinflammatory gene expression following both stimuli. Together, these findings offer new insight into how the arterial microenvironment contributes to atherogenesis, with fibronectin-binding integrin signaling promotes ER stress in response to mechanical and metabolic stressors, thereby amplying proinflammatory endothelial activation through JNK-c-Jun signaling.
Highlights: Fibronectin promotes endothelial ER stress in response to oxLDL and disturbed flow via integrin α5β1 and αvβ3 signaling.Matrix-specific ER stress occurs independently of oxidative stress or misfolded protein accumulation, indicating a non-canonical UPR activation.ER stress amplifies proinflammatory gene expression through JNK-c-Jun signaling, without activating NF-κB.Targeting the integrin-ER stress-JNK axis may offer new therapeutic strategies for early atherosclerosis.

DOI: https://doi.org/10.1101/2025.05.31.654582
J Diabetes Metab Disord. 2024 Dec;23(2): 1601-1612

Importance of unfolded protein response modulation on diabetes management: a systematic review.

Marzieh Nemati, Morvarid Siri, Bahareh Ebrahimi, Zahra Hosseinzadeh, Mina Molayem, Pooneh Mokarram, Sanaz Dastghaib.

   Purpose: The Endoplasmic reticulum (ER) organelle is necessary for protein folding and, in this regard, has a determined capacity. Increased protein synthesis beyond endoplasmic reticulum capacity, leads to ER dyshomeostasis, unfolded proteins accumulation, ER stress, and unfolded protein response (UPR) induction which mediating by three transmembrane sensor proteins. Various studies have shown that in diabetes, greater demand for insulin production is one of the causes of UPR induction giving rise both ameliorative and destructive effects through modulation activity of different branches. Our purpose is to investigate precise role of UPR on diabetes management.
Methods: Inclusion criteria were English language and full text publications. Diseases other than diabetes and mechanisms other than UPR were excluded. Search was done in PubMed, web of science (WOS) and Scopus using keywords.
Results: After assessing bias, total of 22,364 articles were initially identified. Duplication (1593) was deleted using hand- screening, 20,771 papers met all inclusion criteria and selected. Both review and unrelated articles were excluded. Finally, 36 articles assessed for the precise role of the UPR on diabetes management. The most of studies (29) showed improving effects of UPR, (17 studies) investigated activity of only one arm, and protein kinase RNA like endoplasmic reticulum kinase (PERK) was the most investigated (31) arm. Different findings might be explained by different endoplasmic reticulum stress induction strategies, treatment duration, and varied investigations in these studies. We summarize the role of UPR on diabetes management, but despite promising and ameliorating results of this review, further studies are needed to clarify the helpfulness in clinical management of diabetes.

Keywords:  Endoplasmic reticulum; Endoplasmic reticulum stress; Unfolded protein response

DOI:  https://doi.org/10.1007/s40200-024-01451-1
iScience. 2025 Jun 20. 28(6): 112569

Impact of ATF6 deletion on the embryonic brain development.

Loc Dinh Nguyen, Ly Huong Nguyen, Dat Xuan Dao, Tsuyoshi Hattori, Mika Takarada-Iemata, Hiroshi Ishii, Takashi Tamatani, Hiroshi Kawasaki, Yohei Shinmyo, Kenta Onoue, Shigenobu Yonemura, Jun Zhang, Masato Miyake, Seiichi Oyadomari, Kazutoshi Mori, Osamu Hori.

  Although the unfolded protein response (UPR) is activated during brain development, its roles remain unclear. Here, we report that deletion of activating transcription factor 6 (ATF6), consisting of ATF6α and ATF6β, in the developing brain caused microcephaly and neonatal death in mice. Analysis of Atf6a/Atf6b double conditional knockout (dcKO) brains revealed diverse neuronal phenotypes, such as reduced neurogenesis, increased cell death, impaired cortical layer formation, and axon projection defects. Furthermore, hypervasculature, glial defects, and neuroinflammation were observed in dcKO brains. Notably, hypervasculature was detected at E14.5, when endoplasmic reticulum (ER) stress was morphologically unclear, but the UPR was activated to a greater extent in dcKO brains. Expression profiles revealed reduced levels of molecular chaperones in the ER and enhanced levels of PERK- and IRE1-downstream molecules, including VEGFA, in dcKO brains. Administration of a chemical chaperone 4-phenylbutyric acid partially rescued dcKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR.

Keywords:  Cell biology; Developmental biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.112569
Mol Biol Cell. 2025 Jun 11. mbcE25030101

SEL1L Regulates ER Homeostasis in Sertoli Cells but Is Dispensable for Their Function.

Nusrat Jahan Tushi, You Lu, Zhibing Zhang, Shengyi Sun.

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) plays a vital role in maintaining ER homeostasis by degrading misfolded ER proteins. The SEL1L-HRD1 complex, the most evolutionarily conserved branch of ERAD, has been implicated in various physiological processes in both mice and humans, including cellular stress responses, immune function, and development. However, its role in Sertoli cells, which are critical for supporting spermatogenesis, remains unexplored. Here, we show that Sertoli cell SEL1L is not essential for their function or spermatogenesis. SEL1L and HRD1 proteins are expressed in Sertoli cells, and the deletion of SEL1L in Sertoli cells reduces HRD1 protein levels and impairs ERAD function. This leads to elevated ER stress responses and increased expression of ER chaperones, suggesting a potential compensatory adaptation to maintain ER homeostasis. Despite these changes, Sertoli cell-specific Sel1L deletion does not disrupt testicular histology, sperm count, or male fertility. These findings reveal the adaptation of Sertoli cells to SEL1L and ERAD dysfunction and highlight their ability to sustain spermatogenesis under ER stress.

DOI: https://doi.org/10.1091/mbc.E25-03-0101
Mol Ther Oncol. 2025 Jun 18. 33(2): 200995

ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.

Chamanthi Paidi, Yerusha Nuthalapati, Anuveda Sree Samudrala, Priyamvada Bhamidipati, Charanteja Mangam, Danny R Welch, Ganji Purnachandra Nagaraju, RamaRao Malla.

  Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2) activity, enhances BC cell survival. Similarly, ER stress and the unfolded protein response, both modulated by dysregulated ER-mitochondrial contacts, promote drug resistance. In BC, caveolae-dependent and -independent caveolin-1 signaling alongside Yes-associated protein (YAP) signaling pathway alters organelle dynamics by interacting with Drp1 and Mfn2, underscoring their therapeutic potential. This review explores potential therapeutic strategies targeting ER-mitochondrial communications and their potential for hindering BC progression. These strategies include modulating mitochondrial dynamics and promoting controlled ER stress by disrupting aberrant ER-mitochondrial tethering using chemotherapeutics, clinical inhibitors, and natural compounds, alone or in combination. Ultimately, targeting dysregulated ER-mitochondrial tethering has significant potential to improve patient outcomes in BC.

Keywords:  ER-mitochondria tethering; MT: Regular Issue; ROS; YAP; breast cancer; caveolin-1

DOI:  https://doi.org/10.1016/j.omton.2025.200995
bioRxiv. 2025 Jun 08. pii: 2025.06.04.657944. [Epub ahead of print]

Single-cell transcriptomics showed that maternal PCB exposure dysregulated ER stress-mediated cell type-specific responses in the liver of female offspring.

Joe Lim, Youjun Suh, Xueshu Li, Rebecca Wilson, Hans-Joachim Lehmler, Pamela Lein, Julia Yue Cui.

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. While PCB exposure has been associated with metabolic and neurodevelopmental disorders, its cell type-specific effects on liver development remain poorly understood. This study aimed to investigate how maternal exposure to an environmentally relevant Fox River PCB mixture affects liver development in female offspring at single-cell resolution. We hypothesized that early-life PCB exposure disrupts hepatic metabolic and immune function in a cell type-specific manner. Using single-cell RNA sequencing (scRNA-seq) on liver tissue from postnatal day 28 female mice perinatally exposed to PCBs, we identified major hepatic and immune cell populations and assessed cell-specific transcriptional responses. PCB exposure significantly altered the proportions of endothelial cells and Kupffer cells and reduced neutrophil abundance. Transcriptomic analysis revealed that PCBs dysregulated key pathways in hepatocytes and non-parenchymal cells, including ER stress responses, drug metabolism, and glucose/insulin signaling. Notably, hepatocytes exhibited upregulation of phase-I drug-metabolizing enzymes and uptake transporters, but downregulation of phase-II enzymes and efflux transporters. Kupffer cells and endothelial cells had altered immune and metabolic gene expression, and intercellular communication analysis predicted disrupted fibronectin, collagen, and chemokine signaling due to PCB exposure. RT-qPCR validation confirmed increased hepatic ER stress marker expression. Together these findings demonstrate that perinatal PCB exposure induces persistent, cell type-specific transcriptomic reprogramming in the liver, impairing metabolic and immune functions. This study highlights the utility of single-cell transcriptomics for revealing toxicant effects with cellular precision during critical windows of development.

DOI: https://doi.org/10.1101/2025.06.04.657944
Mol Med. 2025 Jun 11. 31(1): 233

Celastrol improves endothelial function in diet-induced obesity mice via attenuating endoplasmic reticulum stress through the activation of AMPK pathway.

Cheng Yu, Weihong Lin, Jing Yang, Qiong Jiang, Wenkun Liu, Hongjin Liu, Yong Lin, Litao Wang, Lei Chen, Yu Huang, Lianglong Chen.

   BACKGROUND: Diet-induced obesity (DIO) is a significant factor in endothelial dysfunction. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has shown promise as a protective agent against cardiovascular disease. However, the specific protective effects and mechanisms of celastrol in preventing endothelial dysfunction in diet-induced obesity are not yet fully understood.
METHODS AND RESULTS: In this study, eight-week-old C57BL/6 mice were fed a normal or high-fat diet and treated with or without celastrol for 8 weeks. We measured acetylcholine-induced endothelium-dependent relaxation (EDR) in the aortae using a wire myograph. The results revealed that EDR was impaired in DIO mice, along with decreased AMPK phosphorylation, increased endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) in the aortae. These effects were reversed by celastrol treatment. Celastrol also reversed tunicamycin-induced ER stress, decreased nitric oxide (NO) production, and impaired EDR in mouse aortae. The protective effects of celastrol were negated by co-treatment with an AMPK inhibitor (Compound C). Furthermore, in AMPKα deficient mice, the beneficial effects of celastrol on EDR were significantly reduced.
CONCLUSIONS: These findings suggest that celastrol improves endothelial function by inhibiting ER stress and increasing NO production through the activation of the AMPK pathway in DIO mice.

Keywords:  AMPK; Celastrol; Endoplasmic reticulum stress; Endothelial function; Obesity

DOI:  https://doi.org/10.1186/s10020-025-01259-6
Cell Rep. 2025 Jun 11. pii: S2211-1247(25)00605-9. [Epub ahead of print]44(6): 115834

VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.

Gitanjali Roy, Andrea Ordóñez, Derk D Binns, Karina Rodrigues-Dos-Santos, Michael B Kwakye, George C King, Rachel L Kuntz, Noyonika Mukherjee, Andrew T Templin, Zhiyong Tan, Timothy I Richardson, Emma H Doud, Amber L Mosley, Kathryn L Schueler, Christopher H Emfinger, Alan D Attie, Mark P Keller, Travis S Johnson, Michael A Kalwat.

  β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca2+ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However, immunostaining of the T2D human pancreas shows altered distributions of the ratios of the core ERAD components SEL1L, HRD1, and DERL3 in β cells. This work provides a detailed mechanistic characterization of a hypersecretion-specific stress response, revealing potential therapeutic targets, including VDAC1 and ERAD, for modulating β cell function and survival in disease.

Keywords:  CP: Cell biology; CP: Metabolism; ER stress; ER-associated degradation; congenital hyperinsulinism; diabetes; hypersecretion; insulin secretion; pancreatic islets; target identification; transcriptomics; β cells

DOI:  https://doi.org/10.1016/j.celrep.2025.115834