bims-unfpre 2025-11-09 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–11–09
nine papers selected by
Susan Logue, University of Manitoba

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.
Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.
Crucial roles of GALNT6-mediated O-glycosylation of GRP78/Bip in proliferation of breast cancer cells.
Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide.
Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
TMEM166 negatively regulates unfolded protein response to affect hepatocellular carcinoma cell growth and sorafenib resistance.
HERPUD1 mediates palmitic acid-induced UPR sustaining TNBC aggressiveness and is destabilized by CK2 pharmacological inhibition.
Zinc-Related IZH1 as a Novel Regulator of Endoplasmic Reticulum Homeostasis in Yeast.
TUSC3 regulates ERMA-mediated Mg2+ uptake for synaptic function and neurodevelopment.

Front Mol Neurosci. 2025 ;18 1639114

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.

Zhanguo Su, Lijuan Xiang.

  The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

Keywords:  ER stress; exercise; muscle function; neurodegenerative diseases; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2025.1639114
Pharmacol Rev. 2025 Oct 14. pii: S0031-6997(25)07504-0. [Epub ahead of print]77(6): 100096

Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.

Michael Karin, Ju Youn Kim.

The endoplasmic reticulum (ER) is a dynamic membranous organelle that accounts for nearly half of the total membrane content in hepatocytes and serves as a central hub for protein folding and lipid biosynthesis. Given the liver's essential functions in protein production and secretion, lipid handling, and xenobiotic metabolism, hepatocyte ER homeostasis is essential for systemic metabolic control and health. Metabolic dysfunction-associated steatotic liver disease, which affects nearly 30% of the global population, is strongly linked to hepatic ER stress. Accumulating evidence highlights the unfolded protein response (UPR) as a key mechanistic regulator that integrates proteostasis and metabolic stress, thereby influencing disease progression from simple steatosis to inflammation-driven metabolic dysfunction-associated steatohepatitis (MASH). More recently, ER stress has also been implicated as a driver of MASH-related hepatocellular carcinoma, the most common primary liver cancer. In this review, we provide a comprehensive overview of the dynamic roles of the UPR and ER stress in hepatocytes, with particular emphasis on mechanistic insights derived from murine models of MASH-related hepatocellular carcinoma. We also summarize the current animal models of MASH that depend on hepatic ER stress. Finally, we discuss therapeutic candidates for MASH treatment, whose mechanisms of action involve ER stress and the UPR. SIGNIFICANCE STATEMENT: The endoplasmic reticulum (ER) functions as a central signaling hub, transmitting stress cues to transcriptional and translational programs through activation of the unfolded protein response, which orchestrates adaptive responses required for stress recovery. Given that hepatocytes are the largest cell population responsible for systemic protein distribution through ER-regulated protein synthesis, precise control of hepatic ER stress is essential not only for maintaining normal hepatocyte function but also for developing therapeutic strategies against ER stress-driven metabolic dysfunction-associated steatotic liver disease.

DOI: https://doi.org/10.1016/j.pharmr.2025.100096
Biochem Biophys Res Commun. 2025 Oct 24. pii: S0006-291X(25)01584-0. [Epub ahead of print]790 152868

Crucial roles of GALNT6-mediated O-glycosylation of GRP78/Bip in proliferation of breast cancer cells.

Keiji Uchiyama, Kosei Hagiwara, Yosuke Matsushita, Tetsuro Yoshimaru, Masaya Ono, Mitsunori Sasa, Toyomasa Katagiri.

  Increased expression of the polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), an O-glycosyltransferase, has been reported to play a crucial role in mammary carcinogenesis. Here, we demonstrate that GALNT6 O-glycosylates Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/Bip), a key regulator of the unfolded protein response (UPR), by adding N-acetylgalactosamine (GalNAc), thereby modulating its stability in breast cancer cells. Functional inhibition of either GALNT6 or GRP78/Bip suppressed the proliferation of the luminal-type breast cancer cell line, ZR-75-1, understanding their importance in tumor cell growth. We further found that GRP78/Bip, which is primarily localized in the endoplasmic reticulum (ER), is transported to the Golgi apparatus under the ER stress conditions, where it undergoes O-glycosylation at Thr203 by the Golgi-resident GALNT6. Substitution of Thr203 with alanine inhibited the binding of GRP78/Bip to IRE1, an ER stress sensor, suggesting that the O-glycosylation at Thr203 in GRP78/Bip facilitates sustained activation of the UPR. These findings define the GALNT6-GRP78/Bip axis as a novel mechanism driving persistent UPR activation and tumor cell adaptation to ER stress, offering a potential new therapeutic target for luminal-type breast cancers.

Keywords:  Breast cancer; Endoplasmic reticulum stress; GALNT6; GRP78/Bip; O-Glycosylation

DOI:  https://doi.org/10.1016/j.bbrc.2025.152868
Cell Death Discov. 2025 Nov 06. 11(1): 502

Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide.

Fakiha Firdaus, Osmel Companioni Napoles, Raul Ariel Dulce, Anusha Edupuganti, Surinder Kumar, Khushi Shah, Salih Salihoglu, Derek J Van Booven, Richard Gasca, David B Lombard, Joshua M Hare, Fangliang Zhang, Rehana Qureshi, Himanshu Arora.

Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of prostate cancer characterized by high levels of endoplasmic reticulum (ER) stress and metabolic dysregulation. The subsequential metabolic adaptations in the cancer cells reinforce survival mechanisms that contribute to therapy resistance and metastasis. The oncogenic driver neuroblastoma-derived MYC (MYCN) exacerbates ER stress by increasing calcium ion efflux from the ER into mitochondria, promoting glycolytic and oxidative stress. Here, we demonstrate that nitric oxide (NO) signaling is dysregulated in NEPC, thus allowing impaired S-nitrosylation of MYCN and uncontrolled ER stress. We show that exogenous NO supplementation restores MYCN S-nitrosylation at Cys4, Cys186, and Cys464. This re-establishment significantly reduces ER stress markers, inhibits the unfolded protein response (UPR), and suppresses NEPC cell proliferation and colony formation in vitro. In an orthotopic NEPC murine model, NO treatment led to a substantial reduction in tumor burden and metastasis to the liver and brain, with corresponding decreases in chromogranin and synaptophysin expression. Additionally, NO supplementation attenuated glycolytic stress by limiting calcium-mediated mitochondrial dysfunction and modulating metabolic pathways. Our findings uncover a direct mechanistic link between MYCN-driven ER stress and NEPC progression and highlight NO supplementation as a potential therapeutic strategy to counteract lineage plasticity and metabolic adaptations in NEPC. These results provide a compelling rationale for further investigation into NO-based therapies as a novel intervention for NEPC, a cancer subtype with limited treatment options and poor prognosis.

DOI: https://doi.org/10.1038/s41420-025-02774-5
Cell Death Differ. 2025 Nov 01.

Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.

Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

DOI: https://doi.org/10.1038/s41418-025-01603-7
Cell Death Dis. 2025 Nov 05. 16(1): 794

TMEM166 negatively regulates unfolded protein response to affect hepatocellular carcinoma cell growth and sorafenib resistance.

Tao Li, Jinqiu Feng, Dan Xia, Yaxin Lou, Pengli Guo, Shufang Ye, Zongming Zhang, Yingyu Chen.

Transmembrane protein 166 (TMEM166), an endoplasmic reticulum (ER)-resident membrane protein, exerts anticancer effects by inducing autophagy and apoptosis. Although tissues of various cancers downregulate its expression, the biological function of TMEM166 in hepatocellular carcinoma (HCC) remains unclear. Herein, we report that TMEM166 negatively regulates unfolded protein response (UPR) in HCC. TMEM166 was noted to interact with ACSL3 to maintain ACSL3 stability and facilitate lipid storage. TMEM166 deletion reduced ACSL3 expression and increased lipid utilisation in the mitochondria through fatty acid β-oxidation (FAO), ultimately boosting ATP production. Moreover, TMEM166-knockout (KO) cells demonstrated accelerated protein synthesis via the AMPK-mTOR axis. These effects induced sublethal ER stress and UPR activation in TMEM166-KO cells. Furthermore, TMEM166 KO promoted HCC cell proliferation and sorafenib resistance via UPR activity upregulation. We analysed the clinical significance of TMEM166-regulated UPR in human HCC cells and noted that TMEM166 expression was negatively correlated with the activities of UPR-related transcriptional factors such as ATF4, ATF6 and XBP1s in the cells. This study is the first to elucidate the relationship among TMEM166, ER stress, and HCC and may provide and indicate newer avenues for TMEM166-targeted gene therapy strategies for HCC treatment.

DOI: https://doi.org/10.1038/s41419-025-08176-w
Cell Death Dis. 2025 Nov 05. 16(1): 793

HERPUD1 mediates palmitic acid-induced UPR sustaining TNBC aggressiveness and is destabilized by CK2 pharmacological inhibition.

Laura Hernández-Torres, Viviana A Cavieres, Omar Cortés, Eloisa Arias-Muñoz, Francisca Cruzat-Arias, Jorge Catalán-Aguilera, Javiera Álvarez-Indo, Macarena Aguilera-Olguín, Ronny Hernández, Eduardo Silva-Pavez, Julio C Tapia, Jorge Cancino, Carlos F Lagos, Tammy P Pástor, Abigail J Galarza, Gonzalo A Mardones, Manuel Varas-Godoy, Nicole Villarreal-Cruz, Franz Villarroel-Espindola, Isabel Saffie, Alfonso González, María José Barrera, Pamela Ehrenfeld, Patricia V Burgos.

HERPUD1 is a protein of the endoplasmic reticulum (ER) that is sensitive to the unfolded protein response (UPR) induced during ER stress and has been linked to ER stress tolerance in cancer cells. Many tumors, including triple-negative breast cancer (TNBC), which lacks an effective treatment, display UPR activity as a malignancy trait. However, whether HERPUD1 provides an ER-dependent mechanistic link for tumorigenic agents and/or potential therapeutic targets remains unknown. To address these possibilities, we first analyzed HERPUD1 expression in breast cancer (BC) biopsies via immunohistochemistry and immunofluorescence, revealing significantly higher levels in BC, including luminal A and TNBC, compared to non-malignant tissue. In TNBC, in addition to epithelial cells, HERPUD1 associated with inflammatory infiltrates, highlighting its potential role in tumor progression. Palmitic acid (PA), a dietary saturated fatty acid, is an obesity-associated tumor risk factor that induces ER stress and activates UPR. Interestingly, MDA-MB-231 cells, but not other BC cell lines, specifically upregulate HERPUD1 together with XBP1s and ATF4, key UPR factors, in response to PA, whereas TG treatment elevated HERPUD1 across all tested cell lines. HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. HERPUD1 ablation also elevated UPR activation under TG. In contrast, PA-induced stress led to reduced UPR activation and lower IL-6 and IL-8 levels in the absence of HERPUD1 expression. We identified CK2 as a kinase that regulates HERPUD1 stability via Ser-59 phosphorylation. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression.

DOI: https://doi.org/10.1038/s41419-025-08111-z
Mol Biol Cell. 2025 Nov 05. mbcE25070348

Zinc-Related IZH1 as a Novel Regulator of Endoplasmic Reticulum Homeostasis in Yeast.

Jonathan Palmiero, Lynzie Wilkinson, Arianna Forzano, Amira Aly, Victoria Iuzzolino, Chloe LoSauro, Simrat Mangat, Nicolas McGuire, Rebecca Robinson, Michel Becuwe.

Endoplasmic reticulum (ER) homeostasis is maintained through tightly regulated processes that coordinate lipid metabolism and proteostasis. The ER-resident acyl-CoA diphosphatase FIT2, and its yeast homolog Scs3, are key regulators of this balance; their loss disrupts ER morphology and induces chronic ER stress, though the underlying mechanisms remain unclear. To uncover factors involved in Scs3-dependent ER maintenance, we conducted a genome-wide multicopy suppressor screen in SCS3 knockout yeast cells, which display inositol auxotrophy. This analysis identified IZH1, a zinc-related ER membrane protein homologous to the human PAQR (Progestin and AdipoQ Receptor) family, as a genetic interactor of SCS3. IZH1 overexpression enhanced INO1 expression, partially restored growth of SCS3 knockout cells in inositol-deprived conditions, and reduced ER stress levels without correcting ER morphology defects. Moreover, IZH1 overexpression attenuated unfolded protein response signaling during acute proteotoxic stress and normalized ER-associated degradation kinetics. Together, these findings identify Izh1 as a novel regulator of ER homeostasis and provide new insight into how FIT2/Scs3 influence ER function.

DOI: https://doi.org/10.1091/mbc.E25-07-0348
Nat Commun. 2025 Nov 07. 16(1): 9752

TUSC3 regulates ERMA-mediated Mg2+ uptake for synaptic function and neurodevelopment.

Gyeongrin Park, Namhoon Kim, Seon-Yong Kim, Hyeonjeong Lee, Cathena Meiling Li, Jae Hong Seol, Se-Young Choi, Yong-Keun Jung.

Intellectual disability (ID) is characterized by deficits in cognition and adaptive behavior, with few treatment options. Tumor Suppressor Candidate 3 (TUSC3) has been genetically linked to autosomal recessive ID, but its molecular mechanism and therapeutic potential remain unclear. Here we show that TUSC3 is essential for endoplasmic reticulum (ER) Mg²⁺ homeostasis and neuronal function. Using a TUSC3 knockout (KO) mouse model, we find ID-like phenotypes including impairments in learning, memory, stress adaptation, and social behavior. Mechanistically, TUSC3 forms an ER-localized Mg²⁺ transport complex with ERMA and its loss leads to ER Mg²⁺ depletion, PERK-eIF2α pathway activation, synaptic dysfunction, and neuronal vulnerability. Fibroblasts from TUSC3 mutant patients similarly exhibit ER Mg²⁺ deficiency and heightened ER stress. Magnesium supplementation restores ER Mg²⁺ levels, reduces ER stress, and rescues cognitive deficits. Our findings establish ER Mg²⁺ dysregulation as a key driver of neurodevelopmental dysfunction and a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-65668-1