bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–08–03
seven papers selected by
Susan Logue, University of Manitoba



  1. Biomolecules. 2025 Jun 25. pii: 930. [Epub ahead of print]15(7):
      Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, the ER manages protein folding and redox balance, while lysosomes regulate autophagy and degradation. Cancer cells, however, are frequently exposed to elevated levels of reactive oxygen species (ROS), which disrupt protein folding in the ER and damage lysosomal membranes and enzymes, promoting dysfunction. Persistent OS activates the unfolded protein response (UPR) and contributes to lysosomal membrane permeabilization (LMP), leading to pro-survival autophagy or cell death depending on the context and on the modulation of pathways like PERK, IRE1, and ATF6. Cancer cells exploit these pathways by enhancing their tolerance to OS and shifting UPR signaling toward survival. Moreover, lysosomal impairment due to ROS accumulation compromises autophagy, resulting in the buildup of damaged organelles and further amplifying oxidative damage. This vicious cycle of ROS-induced ER stress and lysosomal dysfunction contributes to tumor progression, therapy resistance, and metabolic adaptation. Thus, targeting lysosomal and ER stress responses offers potential as cancer therapy, particularly in increasing oxidative stress and promoting apoptosis. This review explores the interconnected roles of lysosomal dysfunction, ER stress, and OS in cancer, focusing on the mechanisms driving their crosstalk and its implications for tumor progression and therapeutic resistance.
    Keywords:  ER stress; LMP; autophagy; cancer; lysosomal dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/biom15070930
  2. Redox Biol. 2025 Jun 09. pii: S2213-2317(25)00226-5. [Epub ahead of print]86 103713
      Chronic reductive stress (cRS), induced by constitutive activation of Nrf2 in transgenic (TG) mouse hearts leads to pathological cardiac remodeling and diastolic dysfunction. Transcriptomic analysis revealed that both pro-reductive (PR) and reductive stress (RS) conditions disrupt ER-associated gene expression in a dose-dependent manner, with pronounced dysregulation in high-expressing TG (TGH) mice. These shifts were associated with persistent activation of the unfolded protein response (UPR), impaired ER function, and redox imbalance marked by elevated glutathione and reduced ROS levels. Proteostasis disruption under cRS led to protein misfolding, ER dilation, and aggregation of mis/unfolded proteins. TGH mice showed increased ubiquitination and accumulation of aggregated proteins, alongside inadequate proteasome activity, indicating inadequate protein quality control (PQC) mechanisms. RNA-seq data revealed transcriptional upregulation of ubiquitin-proteasome genes and downregulation of key chaperones, suggesting a failed compensatory response. Speckle-tracking echocardiography (STE) detected myocardial dyssynchrony and progressive strain abnormalities in TGH mice, correlating with increased proteotoxic burden and impaired redox homeostasis. Elevated TEI index values confirmed systolic and diastolic dysfunction. Time- and dose-dependent upregulation of Nogo/Reticulon4 transcripts and proteins further supported maladaptive cardiac remodeling. Collectively, these findings highlight that chronic RS disrupts ER homeostasis, induces proteotoxicity, and impairs cardiac structure and function, particularly in high transgene-expressing hearts.
    Keywords:  Cardiac hypertrophy; Diastolic dysfunction; ER stress; Nrf2 signaling; Proteotoxicity; Reductive stress
    DOI:  https://doi.org/10.1016/j.redox.2025.103713
  3. Am J Respir Cell Mol Biol. 2025 Jul 28.
      Secondary Streptococcus pneumoniae (Spn) infection to influenza A virus (IAV) frequently leads to an increase in morbidity and mortality of IAV. Our recent work establishes that IAV infection disrupts bacterial host defense in the lung epithelium through loss of cystic fibrosis transmembrane conductance regulator protein (CFTR) function, causing an acidification of the ASL and subsequently increasing susceptibility to Spn. Infection with IAV and other respiratory pathogens cause a robust endoplasmic reticulum (ER) stress response. However, the role of this acute ER stress response in predisposing the airway epithelium to susceptibility to bacterial infections remains unknown. Utilizing a primary differentiated human bronchial airway epithelial cell (HBEC) culture system, we find that both IAV-induced ER stress and ER stress alone increase susceptibility to Spn in the airway epithelium and lead to a loss of CFTR activity, subsequently causing a disruption in the rheostatic properties of the airway surface liquid. Importantly, in HBECs without functional CFTR, modulation of ER stress in the presence and absence IAV of has no effect on susceptibility to Spn. Restoration of ASL pH after ER stress in HBECs with functional CFTR reduces Spn, suggesting that ER stress increases susceptibility to bacterial infection by disrupting CFTR and causing an acidification of the ASL. Here, we demonstrate a clear role for ER stress in disruption of both the airway epithelium and bacterial host defense mechanisms during respiratory viral infection.
    Keywords:  Cell stress; Influenza; Viruses; airways; cystic fibrosis
    DOI:  https://doi.org/10.1165/rcmb.2025-0141OC
  4. Sci Rep. 2025 Jul 28. 15(1): 27496
      Since genomics, epigenomics and transcriptomics have provided only a partial explanation of chronic lymphocytic leukaemia (CLL) heterogeneity, and since concordance between mRNA and protein expression is incomplete, we related the CLL proteome to clinical outcome. CLL samples from patients who received fludarabine-containing chemoimmunotherapy were analysed by mass spectrometry (SWATH-MS). One dataset compared pre-treatment samples associated with an optimal versus suboptimal response, while another compared paired samples collected before treatment and at disease progression. eIF2 signalling (pivotal to the unfolded protein response (UPR)), was identified as the most enriched pathway in both datasets (respective z-scores: - 6.245 and 3.317; p < 0.0001), as well as in a fludarabine-resistant CLL cell line established from HG3 cells (z-score: - 2.121; p < 0.0001). Western blotting revealed that fludarabine-resistant HG3 cells expressed higher levels of PERK, which phosphorylates the regulatory eIF2α subunit, and lower levels of BiP, an HSP70 molecular chaperone that inactivates PERK but preferentially binds to misfolded proteins during ER stress. The PERK inhibitor, GSK2606414, sensitised resistant, but not sensitive, HG-3 cells to fludarabine without affecting background cell viability or cytotoxicity induced by the BCL-2 inhibitor venetoclax. These findings identify the UPR as a novel determinant of therapy outcome and disease progression in CLL.
    Keywords:  CLL cells; Drug resistance and disease progression; PERK linked to resistant phenotype; Proteomics; eIF2 signalling
    DOI:  https://doi.org/10.1038/s41598-025-13495-1
  5. Cell Death Dis. 2025 Jul 29. 16(1): 573
      ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ERUPR and mitoUPR has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ERUPR and mitoUPR, with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ERUPR with mitoUPR, a phenotypic contributor in aging and in AD-like neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41419-025-07743-5
  6. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251363050
      Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes - the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.
    Keywords:  endolysosome; endoplasmic reticulum; membrane contact sites; proteostasis; proteotoxic stress
    DOI:  https://doi.org/10.1177/25152564251363050
  7. Int J Cancer. 2025 Aug 01.
      Breast cancer patients who express estrogen receptor α (ER) typically receive endocrine therapy as a first-line treatment. Most ER-positive breast cancer patients initially respond to endocrine therapy, but up to 40% of patients develop resistance over time, and the main mechanism is aberrant activation of ER signaling pathways. Recent research has shown that cancer's uncontrolled proliferative capacity and a hostile microenvironment can induce endoplasmic reticulum (EnR) stress and trigger unfolded protein response (UPR), which plays a crucial role in determining cell fate. Furthermore, increasing evidence suggests that noncoding ribonucleic acids (RNAs), which are involved during the crosstalk between the UPR and ER signaling pathways, play an essential role in endocrine resistance. In this review, we provide an overview of long noncoding RNA (lncRNA) that is involved both in endocrine resistance and UPR. We provide new insights into potential treatment strategies to overcome endocrine resistance in ER-positive breast cancer patients by targeting the lncRNA that plays key roles in endocrine resistance and UPR signaling. Finally, we discuss the current state and future directions for targeting lncRNAs to improve clinical outcomes in endocrine-resistant breast cancer patients.
    Keywords:  breast cancer; endocrine resistance; long noncoding RNA; unfolded protein response
    DOI:  https://doi.org/10.1002/ijc.70067