bims-unfpre 2025-10-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–10–12
twelve papers selected by
Susan Logue, University of Manitoba

Molecular interplay between oxidative and endoplasmic reticulum stress in multiple sclerosis.
AI662270/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction.
Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells.
IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer.
SCYL1 deficiency in CALFAN syndrome is associated with ER stress and cell death.
UFM1 at the endoplasmic reticulum: linking ER stress, ribosome quality control, and ER-phagy.
Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis.
Atg16l1 and Xbp1 cooperatively protect from transcription-associated mutagenesis and small intestinal carcinogenesis.
ER biogenesis without stress: how the ribosome receptor, p180, defines a developmental program beyond the UPR.
Human immunodeficiency virus 1 glycoprotein 120 induces endoplasmic reticulum stress in neurons.
Pre-N and C-terminal extension regions of Arabidopsis HSP90.7 regulate the chaperone activity and ER stress response.
Hyperactive 20S proteasome enhances proteostasis and ERAD in C. elegans via degradation of intrinsically disordered proteins.

Int J Biol Macromol. 2025 Oct 06. pii: S0141-8130(25)08699-4. [Epub ahead of print]330(Pt 2): 148142

Molecular interplay between oxidative and endoplasmic reticulum stress in multiple sclerosis.

Maryam Kamarehei, Hamid Zahednasab.

  Multiple sclerosis (MS) is a debilitating neurological condition driven by immune-mediated damage to the central nervous system (CNS), leading to myelin destruction and progressive nerve fiber impairment. Recent studies have identified oxidative stress and endoplasmic reticulum (ER) stress as pivotal contributors to MS pathology. When antioxidant defenses fail to neutralize excessive reactive oxygen species (ROS), oxidative damage occurs, harming lipids, proteins, and DNA within neural cells. This oxidative injury worsens mitochondrial dysfunction and sustains chronic inflammation, accelerating disease advancement. Meanwhile, ER stress emerges when misfolded proteins overload the organelle's folding capacity, prompting the unfolded protein response (UPR) to mitigate the crisis. However, prolonged ER stress can shift cellular signaling toward apoptosis, particularly damaging oligodendrocytes and axons in MS. A critical bidirectional relationship exists between these stress pathways-oxidative disturbances disrupt ER protein folding and calcium balance, while unresolved ER stress generates further oxidative radicals. Together, they amplify neuroinflammation, impair glial function, and drive neurodegeneration, making them attractive targets for intervention. Current research explores compounds such as ROS scavengers, ER stress alleviators, and UPR regulators to counteract these mechanisms. Unraveling the interplay between oxidative and ER stress could unlock new treatment avenues to modify MS progression. This review synthesizes current knowledge on their synergistic effects, discusses emerging therapeutic strategies, and highlights gaps for future investigation.

Keywords:  Endoplasmic reticulum stress; Multiple sclerosis; Neuroinflammation; Oxidative stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148142
JCI Insight. 2025 Oct 08. pii: e188904. [Epub ahead of print]10(19):

AI662270/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction.

Suling Ding, Wen Liu, Zhiwei Zhang, Xiyang Yang, Dili Sun, Jianfu Zhu, Xiaowei Zhu, Shijun Wang, Mengshi Xie, Hongyu Shi, Junbo Ge, Xiangdong Yang.

  The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, comprises distinct pathways orchestrated by conserved molecular sensors. Although several of these components have been suggested to protect cardiomyocytes from ischemic injury, their precise functions and mechanisms remain elusive. In this study, we observed a marked increase in glucose-regulated protein 94 (GRP94) expression at the border zone of cardiac infarct in a mouse model. GRP94 overexpression ameliorated post-infarction myocardial damage and reduced infarct size. Conversely, GRP94 deficiency exacerbated myocardial dysfunction and infarct size. Mechanistically, GRP94 alleviated hypoxia-induced mitochondrial fragmentation, whereas its depletion exacerbated this fragmentation. Molecular investigations revealed that GRP94 specifically facilitated the cleavage of Opa1 into L-Opa1, but not S-Opa1. The study further elucidated that under hypoxic conditions, the binding shift of Yy1 from lncRNA Oip5os1 to AI662270 promoted Yy1's binding on the GRP94 promoter, thereby enhancing GRP94 expression. AI662270 attenuated mitochondrial over-fragmentation and ischemic injury after myocardial infarction similarly to GRP94. Moreover, coimmunoprecipitation coupled with LC-MS/MS identified the interaction of GRP94 with Anxa2, which regulates Akt1 signaling to maintain L-Opa1 levels. Overall, these findings unveiled what we believe is a novel role for the AI662270/GRP94 axis in linking ER stress to mitochondrial dynamics regulation, proposing new therapeutic avenues for managing cardiovascular conditions through ER stress modulation.

Keywords:  Cardiology; Cell biology; Cell stress; Hypoxia; Noncoding RNAs

DOI:  https://doi.org/10.1172/jci.insight.188904
Cell Death Discov. 2025 Oct 06. 11(1): 444

Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells.

Lei Zhang, Xuejun Wang.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis. Novel therapeutic strategies for HCC are urgently needed. Ferroptosis, an iron and reactive oxygen species (ROS) dependent regulated cell death, emerges to efficiently abrogate the growth and proliferation of HCC cells. The identification of new ferroptosis inducing agents should provide potential therapeutics for more effective management of HCC. Here we have identified nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor as a novel ferroptosis inducer in HCC cells, Hepa1-6 and HepG2. Mechanistically, the induction of ferroptosis by nelfinavir required its induction of ER stress; suppression of ER stress remarkably attenuated mitochondrial impairment and superoxide production, the autophagic degradation of GPX4, and increases in the labile iron pool associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis in nelfinavir-treated HCC cells. In a mouse model of HCC xenografts, nelfinavir treatment significantly suppressed tumor growth, and this effect was more pronounced when nelfinavir and sorafenib were administered together. Collectively, we demonstrate that nelfinavir can induce ferroptosis in an ER stress dependent manner, thereby identifying a new inducer of ferroptosis that can potentially be repurposed to treat HCC.

DOI: https://doi.org/10.1038/s41420-025-02761-w
Cell Death Dis. 2025 Oct 06. 16(1): 680

IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer.

Yuan Luo, Mengqi Sun, Lei Chang, Zinan He, Xinghang Zhou, Yaming Yuan, Huijuan Sun, Shiqi Luo, Jinyan Huang, Hongkun Wu, Wenjun Liu, Zhangsen Zhou, Yuanhui Mao, Yewei Ji, Tingbo Liang.

Chemotherapy remains a standard treatment for pancreatic ductal adenocarcinoma (PDAC); however, its effectiveness is limited, and the underlying mechanisms are poorly understood. STING plays diverse and critical roles in cancer, yet the role of PDAC cell-intrinsic STING signaling and its regulation under chemotherapy remain unclear. Here, we report that chemotherapy induces cancer cell-intrinsic STING signaling and that STING deletion in PDAC enhances cell death under chemotherapy while suppressing tumor growth in both immune-deficient and immune-competent mice. Interestingly, chemotherapy selectively inhibits translation of IRE1α, an ER membrane protein and a canonical mediator of ER stress. Loss of IRE1α in PDAC amplifies STING signaling and increases resistance to chemotherapy. Mechanistically, IRE1α interacts with STING via their transmembrane regions, reducing STING stability in PDAC cells. Our study reveals that PDAC cells downregulate IRE1α to reinforce STING-mediated pro-survival response; however, this adaptation also makes them more vulnerable to proteostasis imbalance and ER stress-induced cell death. Notably, we demonstrate that combining ER stress inducers with STING signaling inhibition enhances chemotherapy efficacy both in vitro and in vivo.

DOI: https://doi.org/10.1038/s41419-025-07999-x
Dis Model Mech. 2025 Oct 08. pii: dmm.052371. [Epub ahead of print]

SCYL1 deficiency in CALFAN syndrome is associated with ER stress and cell death.

John Hellicar, Tal Dattner, Tian Sun, Lily Percival, Ruby Chrisp, Andrea Pietrobattista, Tomasz Witkos, Aleksander Mironov, Lina Leghlam, Carolin Jentsch, Stefan Koelker, Georg F Hoffmann, Christian Staufner, Wanjin Hong, Dominic Lenz, Martin Lowe.

  CALFAN syndrome is a rare genetic disorder affecting the nervous system and liver, with skeletal abnormalities also reported. It is caused by mutations in the gene encoding SCYL1, a ubiquitously expressed protein localized to the secretory pathway. SCYL1 interacts with trafficking components including ARF GTPases and the COPI vesicle coat complex and appears to function in retrograde secretory trafficking. Despite this knowledge, the mechanisms that underlie CALFAN pathology remain poorly understood. Here, using CALFAN patient and SCYL1 knockout fibroblasts we reveal an accumulation of the abundant secretory cargo procollagen type I in the endoplasmic reticulum (ER) upon SCYL1 deficiency. Surprisingly, we failed to observe procollagen-I trafficking defects in the SCYL1-deficient cells. Nevertheless, ER accumulation of procollagen-I correlated with ER distension and induction of ER stress in the patient fibroblasts, which also underwent increased cell death. The phenotypes were observed at elevated temperature, mimicking the induction of pathology under febrile conditions in CALFAN patients. Our data suggest that ER stress induction is a pathological mechanism in CALFAN syndrome, and that targeting this process may represent a therapeutic strategy.

Keywords:  CALFAN syndrome; ER stress; Golgi apparatus; Procollagen; SCYL1; Secretory pathway

DOI:  https://doi.org/10.1242/dmm.052371
Essays Biochem. 2025 Oct 09. pii: EBC20253054. [Epub ahead of print]

UFM1 at the endoplasmic reticulum: linking ER stress, ribosome quality control, and ER-phagy.

Masaaki Komatsu, Gaoxin Mao.

  Ubiquitin-fold modifier 1 (UFM1) is a small protein that functions as a ubiquitin-like modifier attached to other proteins to alter their behavior. Although less famous than ubiquitin, UFM1 has gained attention as a key regulator of proteostasis (protein homeostasis) in the cell. Notably, the endoplasmic reticulum (ER) has emerged as the central stage for UFM1's activity. UFM1 was initially recognized for its role in the ER stress response, and we now know it orchestrates two critical quality-control processes at the ER: ribosome-associated quality control and selective autophagy of the ER. Together, these mechanisms ensure that the cell can cope with misfolded proteins and stalled ribosomes, maintaining the health of the ER and the proteins it produces. In this review, we will explore how UFM1 works at the ER, how its components are regulated during stress, how it facilitates both immediate quality control and longer-term ER turnover, and how disruptions in this system lead to disease, especially in the nervous system.

Keywords:  encephalopathy; endoplasmic reticulum; proteostasis

DOI:  https://doi.org/10.1042/EBC20253054
Int J Med Sci. 2025 ;22(15): 4102-4118

Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis.

Fitria Sari Wulandari, Chih-Yang Wang, Sachin Kumar, Ngoc Phung Ly, Juan Lorell Ngadio, Dahlak Daniel Solomon, Do Thi Minh Xuan, Gabriela Natasha Sutandi, Hung-Yun Lin, Hui-Ru Lin, Yung-Kuo Lee, Hao-Chien Yang, Ming-Cheng Tsai, Ching-Chung Ko.

  Glioblastoma multiforme (GBM) is characterized by rapid progression, therapeutic resistance, and a profoundly immunosuppressive tumor microenvironment. Emerging evidence suggests that endoplasmic reticulum (ER)-associated macromolecules play critical roles in tumor adaptation. In this study, we performed a multi-omics investigation of orosomucoid-like protein 2 (ORMDL2), a conserved ER membrane protein involved in sphingolipid biosynthesis and ER stress regulation, and uncovered its regulatory functions in GBM progression. Transcriptomic analyses across The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) revealed elevated ORMDL2 expression in GBM tissues which causes poor prognosis. The MetaCore pathway and Gene Set Enrichment Analysis (GSEA) identified ORMDL2's involvement in antigen presentation via a major histocompatibility complex I (MHC class I), unfolded protein response (UPR), and mitochondrial apoptotic signaling. Single-cell RNA-sequencing data and the Human Protein Atlas showed ORMDL2 enrichment in tumor stromal cells. Pharmacogenomic correlation via the Genomics in Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) database suggested that ORMDL2 expression was associated with resistance to DNA damage response inhibitors such as etoposide, doxorubicin, talazoparib, and might interact with sphingolipid-targeting compounds. Collectively, our findings establish ORMDL2 as a multi-functional macromolecular regulator of immune suppression and therapeutic resistance in GBM, providing new mechanistic insights and potential targets for translational medicines.

Keywords:  Drug Discovery; Glioblastoma; Multi-omics Analysis; ORMDL2; Tumor Microenvironment (TME)

DOI:  https://doi.org/10.7150/ijms.116954
Oncogene. 2025 Oct 07.

Atg16l1 and Xbp1 cooperatively protect from transcription-associated mutagenesis and small intestinal carcinogenesis.

Nassim Kakavand, Hang Xiang, Georg Laue, Taous Mekdoud, Lina Welz, Miguel Gomes Silva, Joana P Bernardes, Go Ito, Silke van den Bossche, Julia Kugler, Florian Tran, Alexander Ossysek, Simon Imm, Finn Hinrichsen, Moritz Jesinghaus, Arthur Kaser, Richard Blumberg, Timon E Adolph, Stefan Schreiber, Markus Tschurtschenthaler, Philip Rosenstiel, Konrad Aden.

Atg16l1 plays a critical role in autophagy, and Xbp1 is part of the endoplasmic reticulum (ER) homeostasis. Both, Atg16l1 and Xbp1 are known risk genes for inflammatory bowel disease (IBD). Previous studies have shown that dysfunctional Atg16l1 and Xbp1 are epithelial-derived drivers of small intestinal inflammation. Despite a clear link between Crohn's disease and small intestinal adenocarcinoma, the molecular impact of autophagy and ER stress in this malignant transformation is not known. Using a model of impaired ribonucleotide excision repair (RER), a key homeostatic repair mechanism in highly proliferative cells, we investigated the impact of Atg16l1 on epithelial DNA damage responses and small intestinal carcinogenesis with and without functional ER homeostasis. We used conditional mouse models for deficient RER (Rnaseh2bΔIEC), bearing a co-deletion of disrupted autophagy (Atg16l1/Rnaseh2bΔIEC) or ER stress resolution (Xbp1/Rnaseh2bΔIEC), and triple-conditional knock-out mice for both, Xbp1 and Atg16l1 (Atg16l1/Xbp1/Rnaseh2bΔIEC). We assessed the degree of DNA damage and the incidence of small intestinal carcinoma. We report that defective epithelial RER induces autophagy, and that dysfunctional autophagy increases RER-induced DNA damage and causes the loss of RER-induced proliferative arrest but no spontaneous carcinogenesis in the gut. We demonstrate that dysfunctional Atg16l1 drastically increases the incidence of spontaneous intestinal adenocarcinomas in mice with defective epithelial RER and impaired ER homeostasis. We provide experimental evidence that the same epithelial mechanisms suppressing gut inflammation also critically protect from small intestinal carcinogenesis. Our findings set a molecular framework for the increased risk of intestinal carcinogenesis in patients with IBD, which links perturbations of ER homeostasis and autophagy defects with accumulating DNA damage. In a model of transcription-associated mutagenesis, deficiency of the IBD risk gene Atg16l1 does not induce small intestinal cancer. In contrast, double deficiency of Xbp1 and Atg16l1 drives spontaneous tumor formation highlighting a cooperative role of Xbp1 and Atg16l1 in tumor suppression.

DOI: https://doi.org/10.1038/s41388-025-03591-x
Front Cell Dev Biol. 2025 ;13 1682420

ER biogenesis without stress: how the ribosome receptor, p180, defines a developmental program beyond the UPR.

Payam Benyamini, David I Meyer.

  The endoplasmic reticulum (ER) plays a central role in protein and lipid biosynthesis, quality control, and secretion. While its functional roles are well characterized, the mechanisms underlying ER biogenesis remain less defined. Developmental transitions in secretory tissues such as liver, pancreas, mammary gland, and plasma cells illustrate the remarkable capacity to expand their ER network in response to physiological demand. Central to this process is the ribosome receptor p180, a vertebrate-specific integral ER membrane protein whose expression is both necessary and sufficient for rough ER proliferation. Studies in yeast first demonstrated that overexpression of membrane proteins, including HMG-CoA reductase and domains of p180, induces membrane proliferation, thereby establishing yeast as a tractable model for ER biogenesis. In mammalian systems, p180 uniquely links membrane protein expression with biosynthetic scaling, enhancing ribosome binding, mRNA stabilization, lipid biosynthesis, and Golgi biogenesis. Gain- and loss-of-function approaches in human monocytic THP-1 cells confirm that p180 is indispensable for establishing a high-capacity secretory cells phenotype, coordinating the transition from sparse to abundant rough ER and secretory output. Importantly, p180-driven ER proliferation occurs independently of the unfolded protein response (UPR), highlighting distinct yet complementary mechanisms of ER remodeling: p180 as a constitutive biosynthetic scaffold and the UPR as a stress-induced regulator. Together, these findings position p180 as a master determinant of secretory architecture, with implications for development, immunity, and disease. Understanding the molecular underpinnings of p180 function and its integration with lipid metabolism and translation control will advance both basic cell biology and therapeutic strategies targeting secretory dysfunction. Recent work also suggests that p180-mediated ER expansion is dynamically tuned to nutrient availability and growth factor signaling, further linking organelle biogenesis to cellular metabolism. Dysregulation of p180 expression or function may contribute to a variety of pathological states such as cancer, neuronal dysregulation, and atherosclerosis where ER homeostasis is disrupted. Due to its vertebrate-specific origin, p180 also represents an evolutionary concerved lineage that enabled the diversification of complex secretory systems. Ultimately, dissecting the molecular circuits that govern p180 function promises to refine our understanding of organelle plasticity and to identify novel targets for therapeutic intervention.

Keywords:  P180; endoplasmic reticulum stress; endoplasmic reticulum vesicular trafficking; ribosome receptor; rough ER; rough endoplasmic reticulum; unfolded protein response; upr

DOI:  https://doi.org/10.3389/fcell.2025.1682420
Cell Death Dis. 2025 Oct 06. 16(1): 704

Human immunodeficiency virus 1 glycoprotein 120 induces endoplasmic reticulum stress in neurons.

Christy Agbey, Lee A Campbell, Thieu Phan, Gerard Ahern, Italo Mocchetti.

People living with Human Immunodeficiency Virus (HIV) (PLWH) may develop HIV-associated neurocognitive disorder (HAND) despite the use of antiretroviral therapy. Therefore, more studies are needed to identify novel therapies, which require a better understanding of the molecular and cellular mechanisms underlying HIV neurotoxicity. The HIV envelope protein gp120 causes neuronal degeneration similar to that observed in HAND. One mechanism contributing to gp120-mediated neurotoxicity may involve its ability to inhibit protein processing in the Golgi apparatus and endoplasmic reticulum (ER). To provide data in support to this hypothesis, we have used a variety of experimental approaches to investigate the effect of gp120 on ER dynamics. We first analyzed the levels of ER stress-associated proteins, such as immunoglobulin heavy chain binding protein (BiP) and phosphorylated Inositol-Requiring Enzyme 1 alpha (p-IRE1α) by western blot, as well as ER morphology by electron microscopy in gp120 transgenic (tg) mice. We found that the hippocampus of gp120tg mice exhibits an increase of BiP levels and p-IRE1α, as well as altered ER morphology when compared to wild type mice. We confirmed that gp120 alters ER morphology in neurons by using rat cortical neurons in culture. The effect of gp120 was chemokine-co-receptor dependent because AMD3100, a CXCR4 receptor antagonist, abolished the effect of gp120 on BiP immunoreactivity. Moreover, using Gluc-ASARTDL, a reporter protein for monitoring ER calcium, and live Ca2+ imaging, we show that gp120 induces ER Ca2+ depletion in neurons. Overall, our data suggest that gp120 promotes ER stress in neurons.

DOI: https://doi.org/10.1038/s41419-025-08032-x
J Biol Chem. 2025 Oct 08. pii: S0021-9258(25)02658-4. [Epub ahead of print] 110806

Pre-N and C-terminal extension regions of Arabidopsis HSP90.7 regulate the chaperone activity and ER stress response.

Jenan Noureddine, Adheip Monikantan Nair, Kenneth Andrei Espinosa, Linlin Fan, Joyce Cheng, Rongmin Zhao.

  The ER-localized molecular chaperone HSP90.7 plays a critical role in maintaining protein homeostasis in plants, particularly under stress conditions. However, the functional roles of its pre-N and C-terminal extension (CTE) regions remain poorly understood. In this study, we integrated molecular dynamics simulations, in vitro biochemical assays, and in vivo mutant analysis to investigate the roles of these regions. Deletion of either region did not affect normal seedling development but conferred pronounced hypersensitivity to endoplasmic reticulum (ER) stress. Molecular dynamics simulations revealed that both the pre-N and CTE form regulatory contacts with HSP90.7's N-terminal, middle, and C-terminal domains, likely modulating the chaperone's global stability and interdomain communication. Consistent with these findings, removing the pre-N region increased ATPase activity and altered ATP-binding kinetics, consistent with prior reports for mammalian GRP94, whereas deleting the CTE diminished ATP-independent holdase function. Thus, our findings highlight a conserved regulatory role of the pre-N across ER-localized HSP90s. Together, our results underscore the significance of the pre-N and CTE regions for HSP90.7's functional cycle and establish their specialized roles in ER homeostasis and plant stress resilience.

Keywords:  Calcium homeostasis; Endoplasmic reticulum (ER); Glucose response protein 94 (GRP94); Molecular chaperone; Plant development; Plant molecular biology; heat shock protein 90 (HSP90)

DOI:  https://doi.org/10.1016/j.jbc.2025.110806
Sci Adv. 2025 Oct 10. 11(41): eadx3014

Hyperactive 20S proteasome enhances proteostasis and ERAD in C. elegans via degradation of intrinsically disordered proteins.

David Salcedo-Tacuma, Nadeem Asad, Md Qamrul Islam, Raymond Anderson, David M Smith.

Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by toxic accumulation of misfolded and intrinsically disordered proteins (IDPs) that overwhelm cellular proteostasis. The proteasome clears these proteins, but its failure in disease remains unclear. We engineered a Caenorhabditis elegans model with a hyperactive 20S proteasome (α3ΔN) for selective 20S activation. α3ΔN markedly enhanced IDP and misfolded protein degradation, reduced oxidative damage, and improved endoplasmic reticulum-associated degradation (ERAD). Aggregation-prone substrates such as vitellogenins and human alpha-1 antitrypsin (ATZ) were efficiently cleared. Integrated proteomic and transcriptomic analyses reveal systemic adaptations featuring increased protein turnover and oxidative stress resistance independent of superoxide dismutases (SODs). Notably, α3ΔN extended life span and stress resistance independently of canonical unfolded protein response (UPR) signaling via xbp-1. These findings substantiate a "20S pathway" of proteostasis that directly alleviates protein aggregation and oxidative stress, offering a promising therapeutic angle for neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.adx3014