bims-unfpre 2025-05-04 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–05–04
ten papers selected by
Susan Logue, University of Manitoba

The Role of ER Stress and the Unfolded Protein Response in Cancer.
Impact of ER stress and the unfolded protein response on Fabry disease.
Activation of the PERK Branch of the UPR as a Strategy for Improving Outcomes in Acute Ischemic Stroke.
Pancreatic exocrine damage induces beta cell stress in zebrafish larvae.
Feedback-responsive cell factories for dynamic modulation of the unfolded protein response.
Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.
Intrinsic amyloid deposition following proteostasis impairment in osteoarthritic chondrocytes: Insights and therapeutic approaches.
Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor.
A natural gene on-off system confers field thermotolerance for grain quality and yield in rice.
A Necrosis Inducer Promotes an Immunogenic Response and Destroys Ovarian Cancers in Mouse Xenografts and Patient Ascites Organoids.

Cancer Genomics Proteomics. 2025 May-Jun;22(3):22(3): 363-381

The Role of ER Stress and the Unfolded Protein Response in Cancer.

Rose Ghemrawi, Sedra Kremesh, Walaa K Mousa, Mostafa Khair.

  Dysregulation of protein synthesis, folding, and secretion leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). While the UPR is essential for cell survival under stress, its chronic activation in cancer cells supports tumorigenesis, metastasis, and chemoresistance by enabling cellular adaptation to hypoxia, nutrient deprivation, and oxidative stress. This review provides a comprehensive overview of the roles of key UPR mediators - binding immunoglobulin protein (BiP), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) - in cancer progression and therapy resistance. Furthermore, it discusses strategies to target UPR pathways, including small molecule inhibitors, gene therapies, natural compounds, and combination therapies, while it evaluates their preclinical and clinical relevance. Finally, it explores how modulating UPR signaling can overcome therapeutic resistance, improve immunotherapy outcomes, and reshape the tumor microenvironment. This review emphasizes the promise of UPR-targeted approaches in enhancing the efficacy of current cancer treatments and achieving better patient outcomes.

Keywords:  Unfolded protein response (UPR); cancer progression; chemoresistance; endoplasmic reticulum stress; review; targeted cancer therapy

DOI:  https://doi.org/10.21873/cgp.20507
EBioMedicine. 2025 Apr 28. pii: S2352-3964(25)00177-X. [Epub ahead of print]115 105733

Impact of ER stress and the unfolded protein response on Fabry disease.

Malte Lenders, Elisa Rudolph, Eva Brand.

  Fabry disease (FD) is a lysosomal storage disorder caused by pathogenic missense and nonsense variants in the α-galactosidase A (GLA) gene, leading to absent or reduced enzyme activity. The resulting lysosomal accumulation of the substrate globotriaosylceramide leads to progressive renal failure, cardiomyopathy with (malignant) cardiac arrhythmias and progressive heart failure as well as recurrent strokes, which significantly limits the life expectancy of patients affected with FD. There is increasing evidence that pathogenic GLA missense variants as well as formally benign GLA variants can cause retention in the endoplasmic reticulum (ER), resulting in ER stress, which in turn triggers an unfolded protein response (UPR) leading to cellular dysregulation including inflammation, irreversible cell damage, and apoptosis. This review aims to provide an update on the pathogenetic significance of ER stress and UPR in FD, current treatment options, including pharmaceutical and chemical chaperones, and an outlook on current research and future treatment options in FD.

Keywords:  Chaperones; Lysosomal storage disorder; Missense variants

DOI:  https://doi.org/10.1016/j.ebiom.2025.105733
ACS Omega. 2025 Apr 22. 10(15): 15461-15470

Activation of the PERK Branch of the UPR as a Strategy for Improving Outcomes in Acute Ischemic Stroke.

Xiangzhu Li, Dongting Lu, Lei Zou, Lijuan Ma, Yukun Yang, Xingyun Quan, Wei Song, Qinlian Ye, Hui-Lun Lu, Ulf Brockmeier, Yanxia Zhou, Guodong Huang, Ya-Chao Wang.

Brain ischemia disrupts endoplasmic reticulum (ER) dynamics, causes ER stress, and triggers the unfolded protein response (UPR). During the UPR, protein kinase RNA-like ER kinase (PERK) phosphorylates eIF2α, shutting down global protein synthesis, inhibits protein synthesis, and provides neuroprotection during acute ischemic stroke. Herein, middle cerebral artery occlusion/reperfusion (MCAO/R) and PERK neuron-specific deletion conditional knockout mice were employed to observe the function and mechanisms of PERK. CCT020312, a novel selective PERK activator, specifically activates PERK and provides neuroprotection both in vivo and in vitro stroke models. Additionally, CCT020312 enhanced neuronal survival and cerebral microvessels and decreased the level of astrogliosis in acute ischemic stroke mice. Furthermore, in vivo experiments demonstrated that CCT020312 not only prevented apoptosis but also enhanced the PERK/p-eIF2α/LC3-II autophagy signaling pathway in MCAO/R mice. In conclusion, our study supports the potential therapeutic value of targeting PERK in acute ischemic stroke, offering a promising strategy for enhancing stroke outcomes through the modulation of protein synthesis and the autophagy pathway.

DOI: https://doi.org/10.1021/acsomega.5c00125
Diabetologia. 2025 Apr 28.

Pancreatic exocrine damage induces beta cell stress in zebrafish larvae.

Noura Faraj, Willem M H Hoogaars, B H Peter Duinkerken, Anouk H G Wolters, Kim Kats, Mette C Dekkers, Arnaud Zaldumbide, Ben N G Giepmans.

   AIMS/HYPOTHESIS: Excessive endoplasmic reticulum (ER) stress in beta cells can impair proliferation and contribute to autoimmune responses such as the destruction of beta cells in type 1 diabetes. Exocrine-beta cell interactions affect beta cell growth and function. Notably, exocrine abnormalities are frequently observed alongside overloaded beta cells in different types of diabetes, suggesting that exocrine stress may induce beta cell ER stress and loss. While a cause-consequence relationship between exocrine stress and beta cell function cannot be addressed in humans, it can be studied in a zebrafish model. Larvae develop a pancreas with a human-like morphology by 120 h post-fertilisation, providing a valuable dynamic model for studying pancreatic interactions. Our aim was to target exocrine cells specifically and address beta cell status using transgenic zebrafish models and reporters.
METHODS: To explore the impact of exocrine damage on beta cell fitness, we generated a novel zebrafish model allowing exocrine pancreas ablation, using a nifurpirinol-nitroreductase system. We subsequently assessed the in vivo effects on beta cells by live-monitoring dynamic cellular events, such as ER stress, apoptosis and changes in beta cell number and volume.
RESULTS: Exocrine damage in zebrafish decreased pancreas volume by approximately 50% and changed its morphology. The resulting exocrine damage induced ER stress in 60-90% of beta cells and resulted in a ~50% reduction in their number.
CONCLUSIONS/INTERPRETATION: The zebrafish model provides a robust platform for investigating the interplay between exocrine cells and beta cells, thereby enhancing further insights into the mechanisms driving pancreatic diseases such as type 1 diabetes.

Keywords:  Beta cell function; Beta cell stress; Diabetes; Exocrine damage; Zebrafish larvae

DOI:  https://doi.org/10.1007/s00125-025-06432-4
Nat Commun. 2025 May 02. 16(1): 4106

Feedback-responsive cell factories for dynamic modulation of the unfolded protein response.

Daniela Barrios, Bhagyashree Bachhav, Wendolyn Carlos-Alcalde, Carlos D Llanos, Wenchang Zhou, Laura Segatori.

Engineering cell factories that support the production of large quantities of protein therapeutics remains a significant biomanufacturing challenge. The overexpression of secretory proteins causes proteotoxic stress, affecting cell viability and protein productivity. Proteotoxic stress leads to the activation of the Unfolded Protein Response (UPR), a series of signal transduction pathways regulating protein quality control mechanisms aimed at restoring homeostasis. Sustained UPR activation culminates with the induction of apoptosis. Current strategies for enhancing the production of therapeutic proteins have focused on the deregulated modulation of key components of the UPR. These strategies have resulted in limited and often protein-specific improvements as they may lead to adaptation and cell toxicity and do not account for natural population heterogeneities. We report here feedback-responsive cell factories that sense proteotoxic stress and, in response, modulate the UPR to enhance stress attenuation and delay cell death, addressing the limitations of current strategies. We demonstrate that our cell engineering approach enables dynamic UPR modulation upon proteotoxic stress. The sense-and-respond systems that mediate dynamic UPR modulation enhance the production of the therapeutic enzyme tissue plasminogen activator and the bispecific antibody blinatumomab. Our feedback-responsive cell factories provide an innovative strategy for dynamically adjusting the innate cellular stress response and enhancing therapeutic protein manufacturing.

DOI: https://doi.org/10.1038/s41467-025-58994-x
Cell Rep. 2025 Apr 30. pii: S2211-1247(25)00403-6. [Epub ahead of print]44(5): 115632

Activation of the endoplasmic reticulum stress regulator IRE1α compromises pulmonary host defenses.

Amit Sharma, Linda M Heffernan, Ky Hoang, Samithamby Jeyaseelan, William N Beavers, Basel H Abuaita.

  The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is associated with lung infections where innate immune cells are drivers for progression and resolution ammatory cytokinesflammation. Yet, the role of IRE1α in pulmonary innate immune host defense during acute respiratory infection remains unexplored. Here, we found that activation of IRE1α in infected lungs compromises immunity against methicillin-resistant Staphylococcus aureus (MRSA)-induced primary and secondary pneumonia. Moreover, activation of IRE1α in MRSA-infected lungs and alveolar macrophages (AMs) leads to exacerbated production of inflammatory mediators followed by cell death. Ablation of myeloid IRE1α or global IRE1α inhibition confers protection against MRSA-induced pneumonia with improved survival, bacterial clearance, cytokine reduction, and lung injury. In addition, loss of myeloid IRE1α protects mice against MRSA-induced secondary to influenza pneumonia by promoting AM survival. Thus, activation of IRE1α is detrimental to pneumonia, and therefore, it shows potential as a target to control excessive unresolved lung inflammation.

Keywords:  CP: Immunology; Eicosanoids; GBPs; PR8; Type II interferons; UPR; USA300

DOI:  https://doi.org/10.1016/j.celrep.2025.115632
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 26. pii: S0925-4439(25)00213-3. [Epub ahead of print] 167865

Intrinsic amyloid deposition following proteostasis impairment in osteoarthritic chondrocytes: Insights and therapeutic approaches.

Veronica Panichi, Paolo Dolzani, Luca Cattini, Francesco Alabiso, Irene Bissoli, Silvia Cetrullo, Marta Columbaro, Flavio Flamigni, Carla Renata Arciola, Giuseppe Filardo, Alessandro Di Martino, Stefania D'Adamo, Rosa Maria Borzì.

  Osteoarthritis (OA) is the most common age-related and degenerative joint disease. Proteostasis and protein quality control (autophagy, unfolded protein response, and the ubiquitin-proteasome system) are pivotal for cellular homeostasis and their impairment leads to protein misfolding and amyloid deposition in aged tissues. We here investigated amyloid deposition in OA. Amyloid fibrils were observed in chondrocytes in ex vivo cartilage samples. The underlying mechanisms were assessed in vitro: chondrocytes and cartilage organ cultures were treated with chloroquine and/or lipopolysaccharide for assessment (Western Blotting, immunohistochemistry, histochemistry cytofluorimetry) of amyloid deposition after induction of ER stress with/without blockage of autophagy. Overall, our data show for the first time that proteostasis impairment leads to intrinsic amyloid deposition in OA chondrocytes. These effects were mitigated by selected polyphenols. In conclusion, amyloidosis could contribute to OA progression, and the failure of proteostasis, a hallmark of aging, represents a promising therapeutic target.

Keywords:  Aging; Amyloid; Cartilage; Nutraceuticals; Osteoarthritis; Proteostasis

DOI:  https://doi.org/10.1016/j.bbadis.2025.167865
Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2426931122

Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor.

Ashley V Bullington, Ilaria Micallo, Bilkish Bajaj, Pankaj Kumar, Netanya Schlamowitz, Aurora Silva, Sebastian Hendrix, Noam Zelcer, Daniel L Kober.

  Site-one protease (S1P) carries out the first proteolytic step to activate membrane-bound effector proteins in the Golgi. S1P matures through an autocatalytic process that begins in the endoplasmic reticulum (ER) and culminates with the displacement of its inhibitory pro-domain by its cofactor, sterol regulatory element binding protein-regulating gene (SPRING). Spatial control of S1P activity and substrate localization underpins signaling pathways governing, among others, lipogenesis, ER stress, and lysosome biogenesis. The factors governing these pathways are activated by S1P-mediated proteolysis upon their regulated transport from the ER to the Golgi. S1P cleaves substrates with the recognition sequence RX(L/I/V)Z, where X is any residue other than Cys or Pro and Z is preferably Leu or Lys. However, the structural basis for substrate recognition by S1P has remained unknown. Here, we used the small molecule PF-429242, a competitive inhibitor of S1P, to investigate substrate recognition by the S1P/SPRING complex. We determined the structure of S1P/SPRING bound to PF-429242 and found that PF-429242 binds S1P in the same pocket that recognizes the substrate's conserved P4 Arg. Further structural analysis suggests that S1P requires a conformation change to accommodate the substrate's P2 (L/I/V) residue. We designed an S1P mutation (I308A) to reduce the steric clash at the P2 position and generated an S1P that was resistant to PF-429242 in biochemical and cell culture assays. Our findings reveal selectivity in the recognition of substrates by S1P and provide a roadmap for the rational design of improved S1P inhibitors.

Keywords:  SPRING; cholesterol; cryo-EM; proteases; site-1-protease

DOI:  https://doi.org/10.1073/pnas.2426931122
Cell. 2025 Apr 20. pii: S0092-8674(25)00413-1. [Epub ahead of print]

A natural gene on-off system confers field thermotolerance for grain quality and yield in rice.

Wei Li, Ke Yang, Chaofan Hu, Waseem Abbas, Jian Zhang, Pengkun Xu, Bo Cheng, Juncheng Zhang, Wenjing Yin, Abdullah Shalmani, Lianghuan Qu, Qingya Lv, Bingchen Li, Yuqing He, Xuelei Lai, Lizhong Xiong, Qifa Zhang, Yibo Li.

  Rising global temperatures threaten crop grain quality and yield; however, how temperature regulates grain quality and how to achieve synergistic thermotolerance for both quality and yield remain unknown. Here, we identified a rice major locus, QT12, which negatively controls grain-quality field thermotolerance by disrupting endosperm storage substance homeostasis through over-activating unfolded protein response (UPR). Natural variations in QT12 and an NF-Y complex form a natural gene on-off system to modulate QT12 expression and thermotolerance. High temperatures weaken NF-YB9/NF-YC10 interactions with NF-YA8, releasing QT12 suppression and triggering quality deterioration. Low QT12 expression confers superior quality and increases elite rice yield up to 1.31-1.93 times under large-scale high-temperature trials. Two trait regulatory haplotypes (TRHs) from co-selected variations of the four genetically unlinked genes in NF-Ys-QT12 were identified for subspecies thermotolerance differentiation. Our work provides mechanistic insights into rice field thermotolerance and offers a proof-of-concept breeding strategy to break stress-growth and yield-quality trade-offs.

Keywords:  IRE1; NF-Ys; QT12; UPR; a natural gene on-off system; field thermotolerance; grain quality and yield; rice; storage substance balance

DOI:  https://doi.org/10.1016/j.cell.2025.04.011
Cancer Lett. 2025 Apr 29. pii: S0304-3835(25)00304-0. [Epub ahead of print] 217738

A Necrosis Inducer Promotes an Immunogenic Response and Destroys Ovarian Cancers in Mouse Xenografts and Patient Ascites Organoids.

Darjan Duraki, Musarrat Jabeen, Chengjian Mao, Lawrence Wang, Santanu Ghosh, Xinyi Dai, Junyao Zhu, Matthew W Boudreau, Erik R Nelson, Paul J Hergenrother, Georgina Cheng, David J Shapiro.

  Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells in vitro. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.

Keywords:  Ovarian cancer; immunogenic cell death; organoid; patient ascites; unfolded protein response

DOI:  https://doi.org/10.1016/j.canlet.2025.217738