bims-unfpre Biomed News
on Unfolded protein response
Issue of 2025–03–02
eight papers selected by
Susan Logue, University of Manitoba
  1. Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.
  2. In Vitro Inhibition of Endoplasmic Reticulum Stress: A Promising Therapeutic Strategy for Patients with Crohn's Disease.
  3. RNA exosome-driven RNA processing instructs the duration of the unfolded protein response.
  4. Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.
  5. PERK-Olating Through Cancer: A Brew of Cellular Decisions.
  6. ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
  7. ER Stress and Viral Defense: Advances and Future Perspectives on Plant Unfolded Protein Response in Pathogenesis.
  8. Dolutegravir induces endoplasmic reticulum stress at the blood-brain barrier.
  1. Nat Rev Nephrol. 2025 Feb 24.
    Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.
    Jae Hyun Byun, Paul F Lebeau, Jackie Trink, Nikhil Uppal, Matthew B Lanktree, Joan C Krepinsky, Richard C Austin.
      The endoplasmic reticulum (ER) has crucial roles in metabolically active cells, including protein translation, protein folding and quality control, lipid biosynthesis, and calcium homeostasis. Adverse metabolic conditions or pathogenic genetic variants that cause misfolding and accumulation of proteins within the ER of kidney cells initiate an injurious process known as ER stress that contributes to kidney disease and its cardiovascular complications. Initiation of ER stress activates the unfolded protein response (UPR), a cellular defence mechanism that functions to restore ER homeostasis. However, severe or chronic ER stress rewires the UPR to activate deleterious pathways that exacerbate inflammation, apoptosis and fibrosis, resulting in kidney injury. This insidious crosstalk between ER stress, UPR activation, oxidative stress and inflammation forms a vicious cycle that drives kidney disease and vascular damage. Furthermore, genetic variants that disrupt protein-folding mechanisms trigger ER stress, as evidenced in autosomal-dominant tubulointerstitial kidney disease and Fabry disease. Emerging therapeutic strategies that enhance protein-folding capacity and reduce the burden of ER stress have shown promising results in kidney diseases. Thus, integrating knowledge of how genetic variants cause protein misfolding and ER stress into clinical practice will enhance treatment strategies and potentially improve outcomes for various kidney diseases and their vascular complications.
    DOI:  https://doi.org/10.1038/s41581-025-00938-1
  2. Cells. 2025 Feb 13. pii: 270. [Epub ahead of print]14(4):
    In Vitro Inhibition of Endoplasmic Reticulum Stress: A Promising Therapeutic Strategy for Patients with Crohn's Disease.
    Bruno Lima Rodrigues, Lívia Bitencourt Pascoal, Lívia Moreira Genaro, Leonardo Saint Clair Assad Warrak, Beatriz Alves Guerra Rodrigues, Andressa Coope, Michel Gardere Camargo, Priscilla de Sene Portel Oliveira, Maria de Lourdes Setsuko Ayrizono, Lício Augusto Velloso, Raquel Franco Leal.
       BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease marked by an abnormal immune response and excessive pro-inflammatory cytokines, leading to impaired protein processing and endoplasmic reticulum (ER) stress. This stress, caused by the accumulation of misfolded proteins, triggers the unfolded protein response (UPR) through IRE1/Xbp-1, PERK/eIF2α, and ATF6 pathways, which are linked to intestinal inflammation. This study aimed to investigate ER stress in CD patients' intestinal mucosa and evaluate phenylbutyrate (PBA) as an ER stress inhibitor.
    METHODS: Colon biopsies from CD patients and controls were cultured under five conditions, including 4-PBA treatments. Real-time PCR, cytokine level, and immunohistochemistry were performed.
    RESULTS: Immunohistochemistry revealed that ER stress was activated in CD patients' intestinal epithelial cells and lamina propria cells. PERK/eIF2α, but not IRE1/Xbp-1 or ATF6, was upregulated in CD patients compared to controls. UPR-related genes (STC2, CALR, HSPA5, HSP90B1) were also elevated in CD patients. PBA treatment significantly reduced ER stress and UPR markers while decreasing apoptotic markers like DDIT3. Pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17, TNF- α, and sCD40L, were significantly reduced after PBA treatment.
    CONCLUSION: ER stress and UPR pathways are activated in CD colonic mucosa, and PBA reduces these markers, suggesting potential therapeutic benefits for CD-related inflammation.
    Keywords:  Crohn’s disease; endoplasmic reticulum stress; unfolded protein response
    DOI:  https://doi.org/10.3390/cells14040270
  3. Nucleic Acids Res. 2025 Feb 08. pii: gkaf088. [Epub ahead of print]53(4):
    RNA exosome-driven RNA processing instructs the duration of the unfolded protein response.
    Laura Matabishi-Bibi, Coralie Goncalves, Anna Babour.
      Upon stresses, cellular compartments initiate adaptive programs meant to restore homeostasis. Dedicated to the resolution of transient perturbations, these pathways are typically maintained at a basal level, activated upon stress, and critically downregulated upon reestablishment of cellular homeostasis. As such, prolonged activation of the unfolded protein response (UPR), a conserved adaptive transcriptional response to defective endoplasmic reticulum (ER) proteostasis, leads to cell death. Here, we elucidate an unanticipated role for the nuclear RNA exosome, an evolutionarily conserved ribonuclease complex that processes multiple classes of RNAs, in the control of UPR duration. Remarkably, the inactivation of Rrp6, an exclusively nuclear catalytic subunit of the RNA exosome, curtails UPR signaling, which is sufficient to promote the cell's resistance to ER stress. Mechanistically, accumulation of unprocessed RNA species diverts the processing machinery that maturates the messenger RNA encoding the master UPR regulator Hac1, thus restricting the UPR. Significantly, Rrp6 expression is naturally dampened upon ER stress, thereby participating in homeostatic UPR deactivation.
    DOI:  https://doi.org/10.1093/nar/gkaf088
  4. Mol Ther. 2025 Feb 24. pii: S1525-0016(25)00095-4. [Epub ahead of print]
    Boosting the X factor: Increasing XBP1s-mediated ER stress signaling protects motor neurons in ALS/FTD.
    Smita Saxena, Sabine Liebscher.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.02.005
  5. Biomolecules. 2025 Feb 08. pii: 248. [Epub ahead of print]15(2):
    PERK-Olating Through Cancer: A Brew of Cellular Decisions.
    Laurent Mazzolini, Christian Touriol.
      The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane protein that plays a multifaceted role in cancer development and progression, influencing tumor growth, metastasis, and cellular stress responses. The activation of PERK represents one of the three signaling pathways induced during the unfolded protein response (UPR), which is triggered, in particular, in tumor cells that constitutively experience various intracellular and extracellular stresses that impair protein folding within the ER. PERK activation can lead to both pro-survival and proapoptotic outcomes, depending on the cellular context and the extent of ER stress. It helps the reprogramming of the gene expression in cancer cells, thereby ensuring survival in the face of oncogenic stress, such as replicative stress and DNA damage, and also microenvironmental challenges, including hypoxia, angiogenesis, and metastasis. Consequently, PERK contributes to tumor initiation, transformation, adaptation to the microenvironment, and chemoresistance. However, sustained PERK activation in cells can also impair cell proliferation and promote apoptotic death by various interconnected processes, including mitochondrial dysfunction, translational inhibition, the accumulation of various cellular stresses, and the specific induction of multifunctional proapoptotic factors, such as CHOP. The dual role of PERK in promoting both tumor progression and suppression makes it a complex target for therapeutic interventions. A comprehensive understanding of the intricacies of PERK pathway activation and their impact is essential for the development of effective therapeutic strategies, particularly in diseases like cancer, where the ER stress response is deregulated in most, if not all, of the solid and liquid tumors. This article provides an overview of the knowledge acquired from the study of animal models of cancer and tumor cell lines cultured in vitro on PERK's intracellular functions and their impact on cancer cells and their microenvironment, thus highlighting potential new therapeutic avenues that could target this protein.
    Keywords:  ER stress; PERK; cancer; cell death; microenvironment; resistance; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/biom15020248
  6. Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00036-4. [Epub ahead of print]
    ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
    Philippe Pihán, Lisa M Ellerby, Claudio Hetz.
      Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.
    Keywords:  ATAD3A; PERK; endoplasmic reticulum stress; mitochondria–ER contact sites (MERCS); spatial translation regulation
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.002
  7. J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00203-0. [Epub ahead of print] 108354
    ER Stress and Viral Defense: Advances and Future Perspectives on Plant Unfolded Protein Response in Pathogenesis.
    Binita Adhikari, Jeanmarie Verchot, Federica Brandizzi, Dae Kwan Ko.
      Viral infections pose significant threats to crop productivity and agricultural sustainability. The frequency and severity of these infections are increasing, and pathogens are evolving rapidly under the influence of climate change. This underscores the importance of exploring the fundamental mechanisms by which plants defend themselves against dynamic viral threats. One such mechanism is the unfolded protein response (UPR), which is activated when the protein folding demand exceeds the capacity of the endoplasmic reticulum (ER), particularly under adverse environmental conditions. While the key regulators of the UPR in response to viral infections have been identified, our understanding of how they modulate the UPR to suppress plant viral infections at the molecular and genetic levels is still in its infancy. Recent findings have shown that, in response to plant viral infections, the UPR swiftly reprograms transcriptional changes to support cellular, metabolic, and physiological processes associated with cell viability. However, the underlying mechanisms and functional outcomes of these changes remain largely unexplored. Here, we highlight recent advances in plant UPR research and summarize key findings related to viral infection-induced UPR, focusing on the balance between pro-survival and pro-death strategies. We also discuss the potential of systems-level approaches to uncover the full extent of the functional link between the UPR and plant responses to viral infections.
    Keywords:  ER stress; anti-viral defense; potexvirus; protein homeostasis; unfolded protein response; viral infections
    DOI:  https://doi.org/10.1016/j.jbc.2025.108354
  8. FASEB J. 2025 Feb 28. 39(4): e70377
    Dolutegravir induces endoplasmic reticulum stress at the blood-brain barrier.
    Chang Huang, Qing Rui Qu, Md Tozammel Hoque, Reina Bendayan.
      Dolutegravir (DTG)-based antiretroviral therapy is the contemporary first-line therapy to treat HIV infection. Despite its efficacy, mounting evidence has suggested a higher risk of neuropsychiatric adverse effect (NPAE) associated with DTG use, with a limited understanding of the underlying mechanisms. Our laboratory has previously reported a toxic effect of DTG but not bictegravir (BTG) in disrupting the blood-brain barrier (BBB) integrity. The current study aimed to investigate the underlying mechanism of DTG toxicity. Primary cultures of mouse brain microvascular endothelial cells were treated with DTG and BTG at therapeutically relevant concentrations. RNA sequencing, qPCR, western blot analysis, and cell stress assays (Ca2+ flux, H2DCFDA, TMRE, MTT) were applied to assess the results. The gene ontology (GO) analysis revealed an enriched transcriptome signature of endoplasmic reticulum (ER) stress following DTG treatment. We demonstrated that therapeutic concentrations of DTG but not BTG activated the ER stress sensor proteins (PERK, IRE1, p-IRE1) and downstream ER stress markers (eIF2α, p-eIF2α, Hspa5, Atf4, Ddit3, Ppp1r15a, Xbp1, spliced-Xbp1). In addition, DTG treatment resulted in a transient Ca2+ flux, an aberrant mitochondrial membrane potential, and a significant increase in reactive oxygen species in treated cells. Furthermore, we found that prior treatment with ER sensor or ER stress inhibitors significantly mitigated the DTG-induced downregulation of tight junction proteins (Zo-1, Ocln, Cldn5) and elevation of pro-inflammatory cytokines and chemokines (Il6, Il23a, Il12b, Cxcl1, Cxcl2). The current study provides valuable insights into DTG-mediated cellular toxicity mechanisms, which may serve as a potential explanation for DTG-associated NPAEs in the clinic.
    Keywords:  antiretroviral drug toxicity; bictegravir; blood–brain barrier; brain inflammation; dolutegravir; endoplasmic reticulum stress
    DOI:  https://doi.org/10.1096/fj.202402677RR
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒02 at 3:52.