bims-unfpre 2026-11-01 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–11–01
ten papers selected by
Susan Logue, University of Manitoba

Ire1-Mediated Unfolded Protein Response and Other Biological Phenomena in Ascomycota Yeasts and Filamentous Fungi.
Dynamics of Endoplasmic Reticulum Stress Responses in Cells with Different Endoplasmic Reticulum Volumes and Senescence States.
β-cell adaptation to increased insulin demand is a swift and dynamic process orchestrated by unfolded protein response.
Methylated GRP94 promotes liver fibrosis progression by enhancing endoplasmic reticulum stress.
Neuroprotectant development from small molecule inhibitors of CHOP/ATF4 expression.
Piezo1-mediated unfolded protein response in goblet cells regulates intestinal mucus barrier homeostasis through the Ca2 +-IRE1α-XBP1 pathway.
REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance.
Protein disulfide Isomerase-A1 as a novel organizer of Endoplasmic reticulum-plasma membrane contacts via reticulon 4.
Endoplasmic reticulum stress in breast cancer metastasis: mechanisms and therapeutic implications.
EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis.

Cells. 2026 Oct 15. pii: 1883. [Epub ahead of print]15(20):

Ire1-Mediated Unfolded Protein Response and Other Biological Phenomena in Ascomycota Yeasts and Filamentous Fungi.

Mohamad Aji Ikhrami, Yukio Kimata.

  Upon dysfunction of the endoplasmic reticulum (ER), namely ER stress, eukaryotic cells commonly change their gene expression profile, resulting in enhanced ER functions. This cytoprotective response is called the unfolded protein response (UPR), whose molecular mechanism was first elucidated in pioneering studies using Saccharomyces cerevisiae. Ire1 is a transmembrane endoribonuclease that acts as an ER stress sensor. While Ire1-dependent unconventional splicing of mRNA encoding Hac1, the transcription factor responsible for UPR, was discovered in the 1990s, the precise mechanisms regulating their production and activation remain under investigation. Studies on Ire1 and Hac1 in other ascomycetes have also advanced, partly from the perspectives of clinical science and industrial applications, thereby uncovering some significant functional differences from those in S. cerevisiae. For instance, many ascomycete species other than S. cerevisiae likely perform regulated Ire1-dependent decay (RIDD), in which mRNAs encoding ER-client proteins are digested to mitigate ER stress. In certain species, Ire1 may preferentially shift its output toward HAC1 mRNA splicing or RIDD, depending on the type of stimulus. This review article provides an overview of classic and recent findings on the regulation and function of Ire1 and its target mRNAs in various ascomycete species.

Keywords:  RNA; endoplasmic reticulum; fungi; stress response; yeast

DOI:  https://doi.org/10.3390/cells15201883
Curr Issues Mol Biol. 2026 Oct 04. pii: 1027. [Epub ahead of print]48(10):

Dynamics of Endoplasmic Reticulum Stress Responses in Cells with Different Endoplasmic Reticulum Volumes and Senescence States.

Aleksandra V Mishina, Alexey Yu Pas'ko, Dmitry V Kolesov, Lyudmila V Kovalenko, Danila M Zaychenko, Sergey G Morozov, Alexey A Moskovtsev.

  The Unfolded Protein Response (UPR) determines cell fate under endoplasmic reticulum (ER) stress, yet its temporal dynamics across different cell types and senescence states re-main poorly understood. In this study, we investigated UPR kinetics in endothelial and T-lymphoblastoid cell lines with distinct ER volumes, as well as in senescent FRSN cells undergoing ER expansion. Variations in ER volume were confirmed via confocal microscopy and flow cytometry. Using the 'gene response time' metric, we demonstrated experimentally and through mathematical modeling that the BiP response kinetics closely correlate with variations in ER volume. Applying this metric to presenescent FRSN cells with a significantly expanded ER, we found that their ER stress response machinery maintained a response time similar to that of exponentially growing FRSN cells, but exhibited a lower amplitude and a prolonged lag phase, leading to chronic ER stress signaling such as a protracted XBP1(S) expression profile. Scanning ion-conductance microscopy (SICM) revealed a significant decrease in the stiffness of the near-surface layer of presenescent cells, reflecting a rarefaction of the actin cortex and possibly cytoplasmic dilution. We propose that this structural remodeling could be associated with active intracellular transport impairment that weakens the temporal 'tethering' of the proteome to the genome upon cellular senescence. Consequently, the stress response machinery fails to scale proportionally with cell enlargement during senescence, creating a state of 'functional dilution'. This prevents enlarged senescent cells from mounting a scaled response, resulting in prolonged stress signaling and increased vulnerability to proteotoxic stress.

Keywords:  cell geometry and volume; cellular senescence; endoplasmic reticulum (ER) stress; gene response time; mathematical modeling; scanning ion-conductance microscopy (SICM); temporal dynamics; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cimb48101027
Cell Commun Signal. 2026 Jul 29. pii: 576. [Epub ahead of print]24(1):

β-cell adaptation to increased insulin demand is a swift and dynamic process orchestrated by unfolded protein response.

Laura Maria Daian, Andrei Mircea Vacaru, Gabriela Tanko, Elena Mirela Lamba, Oana-Ana-Maria Mardare, Luiza Ghila, Simona Chera, Ana-Maria Vacaru.

  Pancreatic β-cells adapt to increased insulin demand through coordinated functional and molecular responses. However, in diabetes, these adaptive pathways eventually fail, driving β-cell dysfunction and demise. One of these pathways is unfolded protein response (UPR), a complex network of sensors and effectors that cooperate to restore endoplasmic reticulum (ER) function under stress. To define the early UPR programs engaged during β-cell adaptation, we employed a murine model of partial β-cell ablation that preserves normoglycemia while imposing an increased secretory workload on the remaining β-cells. Integrating bulk islet transcriptomics with imaging, ultrastructural and physiological analyses, we identified dynamic molecular and functional adaptations during the compensatory phase. The initial transcriptional response was characterised by induction of apoptosis genes and a stress response. This was later replaced by activation of adaptive UPR pathways accompanied by increased insulin processing. Nuclear Atf4 and Xbp1 increased transiently, consistent with engagement of multiple UPR branches through different mechanisms to restore homeostasis. Functionally, partially ablated islets displayed enhanced secretory competence during an acute secondary ER stress challenge, although this adaptive advantage was lost during prolonged stress. Together, these findings define a transient adaptive UPR program that sustains β-cell function during the early response to β-cell loss and provide insight into mechanisms that may be leveraged to enhance β-cell resilience in diabetes.

Keywords:  ER stress; Insulin; RIP-DTR; Unfolded protein response; β-cells adaptation

DOI:  https://doi.org/10.1186/s12964-026-03110-9
Cell Death Dis. 2026 Aug 05. pii: 910. [Epub ahead of print]17(1):

Methylated GRP94 promotes liver fibrosis progression by enhancing endoplasmic reticulum stress.

Xinyi Liu, Kejia Lu, Zitao Jiao, Yahui Zou, Hui Li, Wei Jiang, Xiaowei Zhang.

Liver fibrosis is a crucial and potentially reversible stage in the progression from chronic liver diseases towards liver cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress is closely related to hepatic stellate cell (HSC) activation and liver fibrosis. Liver fibrosis is frequently accompanied by a global increase in hepatic protein methylation. This suggests that there may be potential unexplored connections among ER stress, protein methylation, and liver fibrosis. Here, we identify PRMT1-mediated methylation of the ER chaperone GRP94 at arginine 395 as a critical event that drives HSC activation and liver fibrogenesis. Using proteomic profiling of liver tissues from mouse models induced by carbon tetrachloride (CCl4) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), combined with studies in human hepatic stellate cells (primary HSCs and the LX2 cell line), we identify that methylation of GRP94 stabilizes the protein by inhibiting its ubiquitination. This modification potentiates the PERK-eIF2α-ATF4 arm of the ER stress response, leading to upregulation of the fibrogenic genes ACTA2 and COL1A1 and promoting HSC activation. Pharmacological inhibition of PRMT1 with MS023 reverses GRP94 methylation, suppresses HSC activation, and attenuates fibrosis progression in both cellular systems and murine models. This finding positions the crosstalk between ER stress and protein arginine methylation as a central node in the pathogenesis of liver fibrosis, suggesting that targeting the methylation of GRP94 may be a potential therapeutic strategy of liver fibrosis.

DOI: https://doi.org/10.1038/s41419-026-09159-1
Cell Rep. 2026 Oct 27. pii: S2211-1247(26)01304-5. [Epub ahead of print]45(11): 118225

Neuroprotectant development from small molecule inhibitors of CHOP/ATF4 expression.

Mu Li, Xiaoqin Yan, Hang Yang, Liang Liu, Xue Feng, Fuyun Bian, Haoliang Huang, Roopa Dalal, David E Solow-Cordero, Steve Schow, Dong Liu, Yang Hu.

  Glaucoma is a neurodegenerative disease that is in urgent need of neuroprotective therapies. We previously revealed the critical role of neuronal endoplasmic reticulum (ER) stress induced by optic nerve injury in glaucomatous neurodegeneration. We also demonstrated that modulation of the ATF4-CHOP branch of ER stress provides significant neuroprotection. Here, we present multiple new chemical series identified by high-throughput screening that inhibit ER stress-induced C/EBP homologous protein (CHOP) expression. We perform a structure-activity relationship analysis of one "hit" compound and establish two analogs with potent activities on inhibiting the expression of CHOP and activating transcription factor 4 (ATF4). We further demonstrate their neuroprotective efficacy in two optic neuropathy models; in both models, they increase survival of retinal ganglion cell somata and axons and preserve visual function. Together, this proof-of-concept evidence establishes the new ER stress modulators as promising candidates for further drug development to provide neuroprotective therapy for glaucoma and other optic neuropathies, and potentially for diverse CNS axonopathies.

Keywords:  CHOP; CP: neuroscience; ER stress; glaucoma; neuroprotection; small molecules

DOI:  https://doi.org/10.1016/j.celrep.2026.118225
Clin Transl Med. 2026 Nov;pii: e70886. [Epub ahead of print]16(11):

Piezo1-mediated unfolded protein response in goblet cells regulates intestinal mucus barrier homeostasis through the Ca2 +-IRE1α-XBP1 pathway.

Jiandi Wu, Shaotong Wang, Zhe Wang, Jianhua Fang, Xueyan Li, Qingqing Zhang, Yan Dai, Wenjing Tian, Yize Ma, Gangping Li, Lei Zhang, Yudong Jiang, Xiaohua Hou, Jun Song.

   BACKGROUND: Our previous study revealed that Piezo1 in colonic goblet cells senses mechanical stimuli to regulate the production and secretion of MUC2, but the underlying mechanism remains unclear. Altered endoplasmic reticulum function and the unfolded protein response (UPR), which are critical for MUC2 protein folding and secretion, were observed in goblet cell-specific Piezo1 knockout mice. This study aimed to investigate whether and how Piezo1 in goblet cells modulates mucus barrier function by regulating the UPR.
METHODS: In vitro, LS174T cells were subjected to orbital shaking to simulate fluid shear stress (FSS) stimulation. The expression of UPR-related molecules and MUC2 was detected using real-time PCR, Western blotting, and immunofluorescence staining in the presence or absence of Piezo1 and UPR inhibition. In vivo, goblet cell-specific Piezo1 knockout (cKO) mice were treated with dextran sulphate sodium (DSS) and water avoidance stress (WAS). We analysed changes in goblet cell morphology, mucus layer thickness, UPR-related protein expression and ER structure. In addition, DSS-induced colitis mice were intraperitoneally injected with Yoda1 to activate Piezo1, and alterations in pathological structures and mucus layer thickness were subsequently evaluated.
RESULTS: Compared with PERK or ATF6, FSS activated PIEZO1 and promoted calcium influx, thereby maintaining ER calcium homeostasis and selectively activating the IRE1α-XBP1 signalling pathway. This cascade facilitated MUC2 production, whereas pharmacological inhibition of PIEZO1 or IRE1α expression significantly abolished these effects. Compared with WT mice, cKO mice exhibited aggravated mucus barrier impairment, downregulated IRE1α-XBP1 and aggravated ER swelling under DSS and WAS. In contrast, pharmacological activation of Piezo1 via Yoda1 treatment restored intestinal mucus layer thickness and ameliorated colitis in DSS mice.
CONCLUSIONS: Piezo1 senses mechanical stimulation to maintain ER calcium homeostasis and modulates the UPR via the IRE1α-XBP1 pathway, thereby facilitating MUC2 production in goblet cells and maintaining intestinal mucosal barrier homeostasis.
KEY POINTS: Piezo1 in colonic goblet cells senses intestinal mechanical stimulation and modulates endoplasmic reticulum calcium homeostasis via Ca2+ influx. The Piezo1-Ca2+-IRE1α-XBP1 signaling axis controls Mucin2 synthesis and production to maintain intestinal mucus barrier integrity. Pharmacological activation of Piezo1 by Yoda1 rescues mucus barrier defects, providing a potential therapeutic strategy for gastrointestinal mucosal injury.

Keywords:  IRE1α; Piezo1; XBP1; dextran sulphate sodium; mucus barrier; unfolded protein response; water avoidance stress

DOI:  https://doi.org/10.1002/ctm2.70886
Cancers (Basel). 2026 Oct 17. pii: 3358. [Epub ahead of print]18(20):

REDD1 in Clear Cell Renal Cell Carcinoma: Linking Stress Adaptation, Proteostasis and Therapeutic Resistance.

Sruthi Sureshkumar, Claudia M Espitia, Fangchao Bi, Rui Xiong, Madison E Gamble, Natalie L Hakim, Kevin R Kelly, Jennifer S Carew, Steffan T Nawrocki.

  Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of RCC and is defined by loss of von Hippel-Lindau (VHL) function and dysregulated hypoxia signaling. Hyperactivation of the mTOR pathway is also frequently observed. These factors increase anabolic and protein-synthetic demand leading to proteotoxic stress. To survive under these conditions, ccRCC cells rely on adaptive endoplasmic reticulum (ER) stress responses and autophagy to maintain proteostasis. Regulated in Development and DNA Damage Response 1 (REDD1, also known as DDIT4) is a key stress response protein that integrates hypoxic, metabolic, and ER stress signals to regulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activity and redox homeostasis. REDD1 can either suppress tumor growth through mTOR inhibition or promote survival by facilitating oxidative stress tolerance and autophagy depending on the specific context. In ccRCC, REDD1 expression is driven by VHL loss and HIF stabilization. Yet, mTORC1 activity frequently persists due to dysregulation of upstream repressors such as TSC1/TSC2, direct activating mutations in mTOR, and enhanced growth factor signaling. This paradox underscores the complex interplay between REDD1 and the oncogenic signaling landscape of RCC. Here, we review emerging evidence positioning REDD1 as a pivotal link between hypoxia, mTOR signaling, and ER stress in ccRCC and discuss how therapeutic modulation of this pathway through ER stress inducers, proteasome inhibitors, and p97/valosin-containing protein (VCP) inhibitors may overcome adaptive resistance and improve patient outcomes.

Keywords:  CB-5339; REDD1; clear-cell renal cell carcinoma; endoplasmic reticulum stress; p97/VCP inhibitors; proteostasis; targeted therapeutics; therapeutic resistance; unfolded protein response

DOI:  https://doi.org/10.3390/cancers18203358
Redox Biol. 2026 Oct 24. pii: S2213-2317(26)00455-6. [Epub ahead of print]98 104456

Protein disulfide Isomerase-A1 as a novel organizer of Endoplasmic reticulum-plasma membrane contacts via reticulon 4.

Tiphany C De Bessa, Percillia Vs Oliveira, Sara Ventura, Gabriele Vm Gabriel, Marina S De Bessa, Stefanne Cp da Silva, Victor Debbas, Celio X Santos, Ajay Shah, Francisco Rm Laurindo.

  Endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (ER-PMc) are nanodomains essential for ER functions such as Ca2+ signaling, lipid metabolism, cell signaling and ER stress responses. However, how ER-PMc dynamics relate to protein folding-related ER oxidoreductases is unclear. We hypothesized that ER-PMc are signaling hubs regulated by ER redox chaperones from the Protein Disulfide Isomerase (PDI) family such as PDIA1. We show that PDIA1 co-localizes with ER-PMc and co-immunoprecipitates with the scaffold protein extended synaptotagmin-3 (E-Syt3). E-Syt3 overexpression increases levels of the ER-shaping protein Reticulon-4 (RTN4), which promotes tubular ER formation, and switches RTN4B1 to B2 isoform. These effects occur in parallel with the increased number of ER-PMc, while PDIA1 secretion is mildly impaired, rather than increased. Importantly, PDIA1 silencing increases number and decreases size of ER-PMc, while affecting ER morphology and tubulation and down-regulating RTN4-B expression. Conversely, RTN4 silencing impairs PDIA1 association with ER-PMc. This indicates that PDIA1 sustains RTN4-B-driven ER tubulation and ER-PMc stability, while RTN4 supports PDIA1 targeting to ER-PMc. Functionally, PDIA1 silencing markedly reduces cytosolic calcium influx, and IP3 receptor activation. Together, our findings position PDIA1 as an integral component and new functional organizer of ER-PMc sites. We propose a model in which ER proteostasis, via PDIA1, converges with ER morpho-structure, via RTN4, to integrate redox and Ca2+ signaling at ER-PM interfaces.

Keywords:  E-Syt3; Endoplasmic reticulum; PDIA1; Plasma membrane contact; RTN4

DOI:  https://doi.org/10.1016/j.redox.2026.104456
J Pharm Pharmacol. 2026 Oct 01. pii: rgag127. [Epub ahead of print]78(10):

Endoplasmic reticulum stress in breast cancer metastasis: mechanisms and therapeutic implications.

Rujie Xu, Wenxin Foo, Lihua Luo, Xu Liu.

   OBJECTIVES: To summarize the roles of endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) in breast cancer (BC) invasion and metastasis and discuss the therapeutic potential of targeting these processes.
METHODS: This review examines the molecular mechanisms linking ERS/UPR signaling to BC progression and synthesizes ERS-targeted anti-metastatic strategies reported over the past decade, including pathway inhibition, ERS hyperactivation, induction of immunogenic cell death, and combination approaches.
KEY FINDINGS: ERS is an adaptive response to adverse conditions within the tumor microenvironment (TME), including hypoxia and nutrient deprivation. ERS/UPR signaling can reshape tumor cell behavior and the TME to promote invasion and metastasis. Clinically, elevated ERS activity is associated with poor prognosis, shorter survival, and reduced therapeutic responsiveness. Therapeutic strategies include inhibiting pro-survival ERS pathways, hyperactivating ERS to induce tumor cell death, and exploiting ERS to trigger immunogenic cell death. However, the context-dependent and subtype-specific roles of ERS, together with potential on-target toxicity in normal tissues, complicate clinical translation.
CONCLUSIONS: ERS represents a therapeutically actionable vulnerability in metastatic BC. Improved patient stratification using ERS/UPR biomarkers, rational combination regimens, and tumor-selective delivery platforms may help maximize therapeutic efficacy while minimizing systemic toxicity.

Keywords:  breast cancer; cellular mechanism; endoplasmic reticulum stress; therapeutic targets; tumor metastasis

DOI:  https://doi.org/10.1093/jpp/rgag127
Nucleic Acids Res. 2026 Oct 24. pii: gkag1022. [Epub ahead of print]54(20):

EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis.

Zahrat El Oula Hassoun, Loic Ongena, Lionel Condé, Bartimée Galvan, Grégory Fettweis, Michelle Lion, Romuald Soin, Jonathan Bruyr, Florence Lemaitre, Marc Thiry, Emeline Mariavelle, Margaux Claes, Arnaud Blomme, Gerben Menschaert, Jonas Dehairs, Véronique Kruys, Cyril Gueydan, Tina M O'grady, Johannes V Swinnen, Sylvain de Breyne, Théophile Ohlmann, Jean-Claude Twizere, Yvette Habraken, Franck Dequiedt.

FET family proteins (FUS, EWSR1, and TAF15) have garnered significant attention due to their involvement in oncogenic fusions and mutations in various cancers and neurodegenerative disorders. Although these highly conserved RNA-binding proteins are widely described as multifunctional regulators of gene expression, their precise molecular functions remain incompletely understood. Here, we uncover a previously unrecognized role for EWSR1 as a selective translational repressor in cancer cells. EWSR1 specifically targets mRNAs involved in lipid metabolism and endoplasmic reticulum (ER) homeostasis. Loss of EWSR1 disrupts ER morphology and impairs activation of the unfolded protein response of the ER (UPRER). Mechanistically, EWSR1 represses translation upon association with target mRNAs, and its conserved region spanning two arginine-glycine-glycine (RGG) boxes contributes to association with the 40S ribosomal subunit. These findings define a novel role for EWSR1 in post-transcriptional gene regulation and suggest that perturbations in its translational activity may underlie the pathogenesis of FET-associated diseases.

DOI: https://doi.org/10.1093/nar/gkag1022