bims-unfpre 2026-01-18 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–01–18
ten papers selected by
Susan Logue, University of Manitoba

Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications.
DERL3 exacerbates glioblastoma malignancy through endoplasmic reticulum stress-dependent mechanisms.
Chronic ER Stress Disrupts Mitochondrial-Associated ER Membrane Integrity in Corneal Endothelial Cells.
Transient ER stress cell-autonomously promotes beta cell cycling in mice.
A non-canonical role for UPR ER during heat stress in C. elegans.
NRF1 is upregulated by docosahexaenoic acid to ameliorate MASH through the inhibition of ER stress.
Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing.
Regulation of stress tolerance by CREB1 sustains multiple myeloma cell survival.
The diverse forms and roles of the neuronal endoplasmic reticulum.
Expanding roles of N-glycosylation in the endoplasmic reticulum.

FASEB J. 2026 Jan 31. 40(2): e71441

Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications.

Enhui Dai, Dongjie Sun, Yanxiao Zhao, Mengtao Zhang, Yifan Wu, Jiabo Ding.

  The unfolded protein response (UPR) is a cellular stress response mechanism that maintains endoplasmic reticulum (ER) homeostasis through three signaling pathways mediated by IRE1α, PERK, and ATF6 sensors. While UPR's role in viral infections has been well documented, recent studies indicate that intracellular bacterial pathogens have evolved specific mechanisms to hijack UPR signaling for survival and replication. This review examines UPR manipulation strategies employed by major bacterial pathogens, including Brucella, Mycobacterium tuberculosis, Legionella, and Salmonella. These pathogens utilize effector proteins that target specific UPR components: Brucella effectors VceC, BspB, TcpB, and BspL interact with ER chaperones and ERAD machinery; M. tuberculosis proteins Rv0297, ESAT-6, HBHA, and CdhM disrupt calcium homeostasis and alter ER morphology; Legionella Lpg0519 activates atypical ATF6 signaling; and bacterial toxins including cholera toxin bind IRE1α structural motifs for pathway activation. The molecular basis of UPR manipulation includes direct protein-protein interactions, calcium signaling interference, ER morphological disruption, and transcriptional program modulation. Bacterial hijacking of UPR pathways affects ER-phagy processes and host immune responses, facilitating intracellular survival. UPR pathway components serve as potential targets for host-directed therapy against persistent and drug-resistant infections. Small molecule modulators targeting IRE1α kinase activity, PERK inhibitors, and ATF6 pathway regulators may complement conventional antimicrobial approaches. Characterization of these host-pathogen interactions provides insights for developing therapeutic strategies that target bacterial dependencies on cellular stress responses.

Keywords:  bacterial infection; effector proteins; endoplasmic reticulophagy; immune response; therapeutic strategy; unfolded protein response

DOI:  https://doi.org/10.1096/fj.202503547R
Am J Cancer Res. 2025 ;15(12): 5301-5316

DERL3 exacerbates glioblastoma malignancy through endoplasmic reticulum stress-dependent mechanisms.

Shaoqi Du, Shuo Zhang, Chen Li, Shaonan Du, Shu Guan, Shiyang Wang, Zhe Wang, Tao Dong, Xiaolin Ren.

  Gliomas, particularly glioblastoma multiforme (GBM), represent the most prevalent primary intracranial malignancies, characterized by high invasiveness, aggressive proliferation, and poor clinical outcomes. Recent studies have highlighted the critical role of tumor microenvironment interactions and cellular stress responses, including endoplasmic reticulum (ER) stress, in modulating glioma progression. While ER stress can induce autophagy and apoptosis, glioma cells exhibit remarkable plasticity, adapting to stress conditions and exploiting them to promote survival and self-renewal, thereby contributing to therapeutic resistance. In this study, we established an individualized ER stress risk score using glioma transcriptomic data, demonstrating its association with adverse prognosis, aggressive molecular subtypes, and pro-tumorigenic biological functions. Through systematic screening, we identified DERL3 as a core effector gene mediating ER stress adaptation. Functional validation revealed that DERL3 drove glioma proliferation and invasion by binding to and stabilizing Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), consequently activating the NF-κB signaling pathway. These findings elucidate the DERL3-HNRNPA2B1-NF-κB axis as a critical mechanistic link between ER stress adaptation and glioma malignancy. Targeting this axis may offer novel therapeutic strategies to overcome treatment resistance, providing significant translational potential for improving glioma management. This study advances our understanding of stress response mechanisms in tumorigenesis and underscores the clinical relevance of ER stress-related pathways in precision oncology.

Keywords:  DERL3; Endoplasmic reticulum stress; glioblastoma; heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1); tumorigenesis

DOI:  https://doi.org/10.62347/NAGJ4413
bioRxiv. 2026 Jan 10. pii: 2026.01.09.698664. [Epub ahead of print]

Chronic ER Stress Disrupts Mitochondrial-Associated ER Membrane Integrity in Corneal Endothelial Cells.

Stephanie Lee, Stefan Y Kim, H Orhan Akman, Saba Qureshi, Anisha Kasi, William Steidl, Lukas Ritzer, Mariane Price, Francis W Price, Eric A Schon, Varun Kumar.

Purpose: Fuchs' endothelial corneal dystrophy (FECD) is an age-related degenerative disease of the corneal endothelium cells (CEnCs), affecting 4% of the US population over 40. While Endoplasmic reticulum (ER) and mitochondrial stress have been independently associated with FECD pathogenesis, few studies have examined ER-mitochondrial interactions/ER-mitochondrial contact sites/mitochondria-associated ER membrane (MAM), or MAM proteins, and their contribution to ER and mitochondrial stress in FECD. This study aims to characterize alterations in MAMs and identify key MAM proteins associated with ER and mitochondrial stress in FECD.
Method: Human corneal endothelial cell line (HCEnC-21T) and Fuchs' corneal endothelial cell line (F35T) were cultured and subjected to ER stressor tunicamycin (1, 10 μg/ml) for 6 and 24 hours. MAM proteins were isolated by subcellular fractionation, and key ER and mitochondrial-damage-sensor proteins, such as PERK and Parkin, respectively, were identified by immunoblotting. ER-mitochondrial contact sites were quantified using the MAM plasmid and transmission electron microscopy (TEM) in normal and Fuchs cell lines, as well as in human tissues under chronic ER stress.
Results: ER-mitochondrial contact distance significantly increased in Fuchs tissues compared with normal tissues, and a similar increase was observed in 21T cell line after tunicamycin treatment. There was a significant increase in the intensity of the MAM plasmid upon tunicamycin treatment at 6 hours in the 21T cell line compared to the non-treated control. However, MAM plasmid intensity significantly decreased at 24 hours compared to 6 hours post-tunicamycin treatment in 21T cell line. Analysis of MAM function by quantifying phosphatidylserine synthase 1 (PSS1 [gene PTDSS1]) expression in 21T cells showed a reduction in PTDSS1 expression after 24 hours of tunicamycin treatment. ER stress protein PERK and mitochondria damage sensor protein (Parkin) significantly increased in the MAM fraction after tunicamycin at 24 hours in 21T cell line.
Conclusions: Fuchs cell lines and tissues demonstrate decreased ER-mitochondrial interactions/MAMs, which are also seen in 21T cell line after chronic ER stress. Under chronic ER stress, ER and mitochondrial stress mediator proteins are translocated to MAM. This study highlights the importance of MAMs as a potential mediator of ER-mitochondria crosstalk in degenerating corneal endothelial cells for FECD.

DOI: https://doi.org/10.64898/2026.01.09.698664
Diabetologia. 2026 Jan 15.

Transient ER stress cell-autonomously promotes beta cell cycling in mice.

Stephanie Bourgeois, Annelore Van Mulders, Yves Heremans, Gunter Leuckx, Lien Willems, Sophie Coenen, Laure Degroote, Julie Pierreux, Daliya Kancheva, Isabelle Scheyltjens, Kiavash Movahedi, Françoise Carlotti, Eelco de Koning, Xiaoyan Yi, Chiara Vinci, Yue Tong, Miriam Cnop, Harry Heimberg, Nico De Leu, Willem Staels.

   AIMS/HYPOTHESIS: Regenerating endogenous pancreatic beta cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote beta cell regeneration. We aimed to investigate whether recovery from experimental hypovascularisation of the endocrine pancreas could trigger mouse beta cell proliferation.
METHODS: A doxycycline (DOX)-inducible transgenic mouse model was used to induce conditional intra-islet hypovascularisation. In this model, vascular endothelial growth factor (VEGF)-A signalling within pancreatic islets is antagonised through beta cell-specific overexpression of a VEGF-A decoy receptor, soluble fms-like tyrosine kinase 1 (sFLT1). Cessation of sFLT1 overexpression was induced by DOX withdrawal. sFLT1 expression, vessel kinetics and beta cell proliferation upon DOX administration and withdrawal were analysed using quantitative RT-PCR and immunostaining. Single-cell RNA-seq was used to investigate the effects on the islet cells' transcriptome and perform pathway enrichment analysis. RIP-rtTA;TetO-GFP mice were studied in parallel to assess the dependency of cell cycle induction on vessel manipulation. Additionally, in vitro experiments were conducted to further elucidate and validate our in vivo findings.
RESULTS: Serendipitously, we discovered that sFLT1 overexpression in beta cells induces endoplasmic reticulum (ER) stress and activates proliferation-associated pathways. Upon cessation of sFLT1 overexpression, ER stress decreased and beta cell proliferation was promoted independently of vessel recovery, as shown by cumulative BrdU labelling over 7 days (mean ± SEM vs control: 14.3 ± 1.3% vs 5.2 ± 0.6%) during the DOX withdrawal period. Transient GFP overexpression also induced ER stress and a subsequent reduction thereof resulted in increased beta cell proliferation (mean ± SEM vs control: 7.2 ± 0.4% vs 5.1 ± 0.5%). Chemical, transient induction of ER stress in vitro by ER-stress-inducing compounds reproduced this beta cell cycling response, as assessed by cumulative EdU labelling during a 3 day washout period (mean ± SEM vs control: 2.6 ± 0.4% vs 0.8 ± 0.2% for thapsigargin and 3.8 ± 0.9% vs 1.0 ± 0.2% for tunicamycin), which further increased under high-glucose conditions when islets were exposed to thapsigargin (mean ± SEM vs control: 9.0 ± 1.2% vs 2.0 ± 0.4%).
CONCLUSIONS/INTERPRETATION: Our findings uncover a link between transgene (over)expression, ER stress, glucose and cell cycle activation in mouse beta cells.
DATA AND CODE AVAILABILITY: The single-cell RNA-seq data generated in this study are deposited at GEO (NCBI) with accession code GSE274443.

Keywords:  Beta cell proliferation; Diabetes; Endoplasmic reticulum stress; Glucose-dependency; Single-cell RNA sequencing; Unfolded protein response; Vascularisation; sFLT1

DOI:  https://doi.org/10.1007/s00125-025-06649-3
bioRxiv. 2026 Jan 09. pii: 2026.01.08.698479. [Epub ahead of print]

A non-canonical role for UPR ER during heat stress in C. elegans.

Athena Alcala, Toni Castro Torres, Rebecca Aviles Barahona, Phillip A Frankino, Ryo Higuchi-Sanabria, Gilberto Garcia.

Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response (ISR), which reduces global translation under various stress conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteosome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and ER chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPR ER ). Using robust transcriptional reporters in the C. elegans model system, we explore a non-canonical activation of the UPR ER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter tissue communications of stress whereby neuronal or glial activation of the UPR ER can result in heterotypic enhancement of the HSR in peripheral and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole cell and whole organism damage.
Article Summary: A reductionist approach to studying cellular stress responses is critical for dissecting specific molecular and genetic drivers of stress response. However, stress responses are often convergent and overlapping, and these single input and output studies may miss their complex interplay. Many studies have revealed the intricate coordination of stress responses, including the ability of seemingly organelle-specific stress responses, like mitochondrial stress responses, to directly influence cytosolic and ER health. Our study adds to this growing field by describing a unique, bidirectional crosstalk between the cytosolic and ER stress pathways, highlighting systemic coordination of stress resilience.

DOI: https://doi.org/10.64898/2026.01.08.698479
Cell Death Dis. 2026 Jan 16. 17(1): 47

NRF1 is upregulated by docosahexaenoic acid to ameliorate MASH through the inhibition of ER stress.

Mengchi Lin, Hongtao Zhang, Shuai Chen, Jie Zhang, Chenxi Tang, Xin Song, Jiaming Zhou, Zixin Xu, Yali Mu, Hang Zeng, Changqing Yang, Chaohui Yu, Chengfu Xu.

Despite the high prevalence of metabolic dysfunction-associated steatohepatitis (MASH), the number of effective therapeutic targets is limited due to a vague understanding of its intricate pathogenesis. In this study, we reported that the expression of nuclear factor erythroid-derived 2-related factor 1 (NRF1), an endoplasmic reticulum (ER) membrane-bound transcription factor that governs the expression of proteasome subunit genes, was significantly reduced in liver tissues from MAFLD patients and from mice fed a high-fat diet (HFD) for 20 weeks. Liver-specific overexpression of NRF1 in mice markedly ameliorated HFD-driven hepatic steatosis, liver injury and inflammation. Elevated NRF1 expression restored the function of the proteasome, facilitating the degradation of unfolded and nonfunctioning proteins, thereby mitigating ER stress and reducing oxidative stress. Moreover, docosahexaenoic acid (DHA) was found to increase NRF1 expression, contributing to the amelioration of MASH. Mechanistically, DHA inhibited the ubiquitination of NRF1 via the cytoplasmic E3 ligases FBW7 and HRD1 at the ER membrane, thereby preventing its degradation. Liver-specific knockdown of NRF1 abrogated the protective effect of DHA on HFD-driven MASH in mice. Together, our findings underscore the pivotal role of NRF1 in the DHA-mediated amelioration of MASH and suggest that NRF1 is a potential therapeutic target for MASH management.

DOI: https://doi.org/10.1038/s41419-025-08139-1
Sci Adv. 2026 Jan 16. 12(3): eaeb5297

Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing.

Aaron Ming Zhi Tan, Cenk Celik, Stella Yue Ting Lee, Mark Veleba, Caroline S Manzano, Rahim M K Abdul, Guillaume Thibault, Kimberly A Kline.

Enterococcus faecalis is an opportunistic pathogen that thrives in biofilm-associated infections and delays wound healing, yet how it impairs host tissue responses is unclear. Here, we identified extracellular electron transport (EET) as a previously unrecognized source of reactive oxygen species (ROS) in E. faecalis and showed that this activity directly triggers the unfolded protein response (UPR) in epithelial cells and delays epithelial cell migration. ROS detoxification with catalase suppressed E. faecalis-induced UPR and rescued epithelial cell migration, while exogenous hydrogen peroxide was sufficient to restore UPR activation in EET-deficient strains. UPR disruption by pharmacological inhibition also impaired cell migration, highlighting a critical role for UPR homeostasis in wound repair. Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering previously unidentified avenues for therapeutic intervention in chronic infections.

DOI: https://doi.org/10.1126/sciadv.aeb5297
Cell Death Dis. 2026 Jan 16. 17(1): 46

Regulation of stress tolerance by CREB1 sustains multiple myeloma cell survival.

Ruchi Kudalkar, Johnathan Altom, Joshua Galloway, Vincent Manning, Sara Taranto, Francesca Cottini.

Multiple myeloma (MM) cells originate from antibody-producing plasma cells and endure chronic oxidative and proteotoxic stress due to the excessive production of immunoglobulins and free light chains. We previously demonstrated that CD56 (also known as neuronal cell adhesion molecule 1) promotes cAMP-responsive element binding (CREB1) activation in MM cells to drive survival, without fully elucidating its mechanism of action. In this study, we describe the global role of CREB1 in regulating tolerance to cellular stresses in MM. Here, we present data to demonstrate that CREB1 directly or indirectly influences key proteins involved in the clearance of oxidants, the unfolded protein response (UPR), and autophagy. In silico data from real patients with MM showed that patients with high CREB1 expression have greater activation of gene sets associated with endurance of stress. We confirmed by genomic and pharmacological modulation that CREB1 activates the mTOR pathway, halting autophagy, and directly binds to the promoter of NRF2 and PERK, modulating genes involved in oxidation and protein stress adaptation. Of particular importance was the identification of TXNIP among the regulated genes. Notably, the TXNIP gene belongs to the 1q21 cytoband, which is amplified in 30 percent of patients with MM, leading to poor outcomes. We showed for the first time that TXNIP inhibition is also toxic against MM cells, interfering with UPR and autophagy. Thus, our data highlights the essential roles of CREB1 and TXNIP in MM cell survival under chronic stress, providing new insights into MM pathophysiology and novel therapeutic strategies for patients with high-risk disease.

DOI: https://doi.org/10.1038/s41419-025-08246-z
Nat Rev Neurosci. 2026 Jan 13.

The diverse forms and roles of the neuronal endoplasmic reticulum.

Lia G Carvalhais, Koen Kole, Marijn Kuijpers.

Neurons are structurally complex and highly compartmentalized, placing unique demands on organelles to adapt locally and support communication across long distances. The endoplasmic reticulum (ER) meets this challenge through a dynamic and versatile architecture that spans the entire neuron. While specialized ER structures in axons, dendrites and synapses have been recognized for some time, recent work has uncovered new insights into their local functions and interactions with other membranes. In this Review, we highlight how neuronal ER morphology is established in different subcellular domains, including somato-dendritic regions, axons, and presynaptic and postsynaptic sites. These distinct ER structures enable localized functions in Ca2+ signalling, biosynthesis, excitability, regeneration, synaptic transmission and plasticity. We also discuss how perturbations in the ER contribute to neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41583-025-01016-y
Trends Cell Biol. 2026 Jan 14. pii: S0962-8924(25)00265-X. [Epub ahead of print]

Expanding roles of N-glycosylation in the endoplasmic reticulum.

Mengxiao Ma, Rajat Rohatgi.

  N-linked glycosylation in the endoplasmic reticulum (ER), catalyzed by two oligosaccharyltransferase (OST) complexes, has long been viewed as a constitutive post-translational modification. Recent discoveries suggest that OST complexes play a much more plastic and directive role in regulating ER processes. Here, we review this work and focus on one specific mechanism that uses N-glycosylation to regulate the stability of the ER chaperone HSP90B1. This degradative process regulates the cell-surface abundance of multiple signaling receptors that are HSP90B1 clients: toll-like receptors, WNT receptors, and growth factor receptors. This unusual system enables the status of ER-based processes to influence the sensitivity of cells to extracellular signals, with implications for tissue growth and development, inflammation, and immune function.

Keywords:  chaperone; endoplasmic reticulum; glycosylation; oligosaccharyltransferase; signaling receptor; translation

DOI:  https://doi.org/10.1016/j.tcb.2025.12.001